Monthly Archives: June 2020

Those who follow the science behind autism may know that there is an explosion of scientific research happening in the field right now.In January Mount Sinai Hospital published a study that identified 102 genes associated with autism. A paper published in Biological Psychiatry earlier this month suggests that a gene mutation may be linked to autistic behaviors. And arecent government studyfound that children who have an autistic uncle or aunt have a more than doubled risk of being diagnosed with the condition themselves.

At the crux of these studies and so many others are questions about why some people have this very unique type of brain. If you're on the autism spectrum, you're likely to be more intelligent than average, but also to struggle more in social situations. You have skills that can make you excel in many career paths, but are also more likely to face very unique types of employment-based discrimination along the way.

What causes people to develop like this? Is it in our genes, due to environmental factors or caused by some combination of both factors? This question, known colloquially as the "nature versus nurture" debate in biology, is innate to much psychology and sociobiology research. To wit: intelligence, disorders like ADHD, and personality disorders all have aspects that are develpmental or environmental and aspects that are genetic.

To learn more about new research in thenature versus nurture debate for autism, I turned to Temple Grandin for answers and this is the part where I need to add that I'm not neutral about Temple Grandin.

The advocate of humane treatment for livestock, who was the focus of the 2010 movie "Temple Grandin" starring Claire Danes, is a hero of the autism community, for which she has emerged as a major spokesperson. I am also on the autism spectrum and, as such, she is a person to whom I have reached out more than once about questions about issues facing my community. She is unquestionably brilliant, blunt to a fault, passionate about helping people and animals and yet clearly one who does not suffer fools gladly.

She also, as I quickly learned, has a talent for explaining autism in a way that makes it easy for virtually anyone to understand. I suspect the readers of this interview will agree. As always, this interview has been condensed and edited for print.

Let's talk about the genetics of autism. We were talking about a January study done at Mt. Sinai Hospital which found that there are 102 genes associated with autism. Do you tend to agree with it?

Well I have no reason not to agree with the study. Basically, autism is a continuous trait. There's a lot of traits where many many genes contribute just a little bit....Some of the genes were associated with other types of developmental delays. There's also a lot of research that shows that there's a crossover between ADHD and autism. Even in the brain scans, there is crossover. I've got some of those references in the new edition of "The Way I See It." Basically, you have a whole lot of little tiny code variations that contribute a little bit and they all have to do with brain development.

Now, I've told you about my own genome scanning. My genes have been totally scanned. What I found is other health problems I have anxiety, bad skin, bad teeth that showed right up. Simple genetics. But the autism stuff, yeah, I got some of the at-risk genes. It gets back into basic brain development.

I told you about the paper called"Genomic Trade-Offs: Are Autism and Schizophrenia the Steep Price of the Human Brain?" This is a quote from their abstract this isn't the way I would have put it but they said, "The genes that make us mad, make us human." That's a quote out of the abstract of the paper. It's not me saying that. I say that the same genes that make the brain big are also involved with autism and schizophrenia. It's a whole lot of little genes. It's a whole lot of little, I call them code variations. There's actually some argument in the literature to exactly what a gene is. I mean there's simple genetic stuff like brown or black coats on Angus cattle. That's very very simple genetics. That's Mendelian genetics. You need to forget about that.

I also went back and looked up some of the twin studies. Some of these were done ages ago. I found a nice review article on "Heritability of Autism Spectrum Disorders: A Meta-analysis of Twin Studies." It's a nice review article on twin studies. Some of this research is very old.

It sounds like you're saying that you believe nature plays a larger role than nurture in creating autism?

Yes. When it comes to nature, what's been found in twin studies, that when child is brought up anywhere resembling a decent environment, there's a lot of traits where genetics has a big effect on it. You get into a lot of things across the board. I'm going to say a person, what they become, is half-nature and half-nurture. It's the same thing with an animal. Some traits are much more genetic than others. One trait that's really genetic is the tendency to startle. This is true with cattle and horses, like if you open an umbrella suddenly, some horses are going to rear up and hit the roof and others will just flinch. Now what context are you discussing nature and nurture?

I'm talking about the question of when people are born on the autism spectrum, to what degree is that because of their genes and to what degree is that because of environmental factors that influence their neurological development, like the way their raised, the degree to which they're exposed to various potentially intellectually stimulating stimuli, things like that.

Well those things all have an effect. Let's say you took a young autistic kid like me and you did no early intervention. I don't think I would have become a college professor. So in terms of what you might become, maybe I'd be in an institution somewhere if nothing had been done with me.

I wonder the same thing about myself.

Well this is the problem, you see? This is something I tell parents all the time: I talk to a lot of low income families and say, You got a kid, he's two-and-a-half or three years old, he's not talking, he sits in the corner rocking, you've got a problem. I don't care whether you've got an official diagnosis or not, work with this kid now. I suggest that they go to their church group and get some volunteers, and you need to start taking turns playing games with the kid. Just start teaching him words, get down to work with this kids. If he just sits there and vegetates, he ain't going anywhere. So okay, that's an environmental influence there.

But then there's other kids that don't work as hard. Some of them can learn to type independently. I mean both nature and nurture are important in determining what a person could accomplish.

I'm going to just take it animals and people both, I'm going to say half-and-half, in terms of what you become. I talk to educators about the goal of education and say, let's look at where a student is 10 years after high school. Well, 10 years after high school I was doing that big dip vat project that was shown in the movie. That was 10 years after high school almost exactly. Okay if the kid's ending up in jail or some other bad thing, certainly don't want him there.

From a cultural perspective, what do you think the implications of this are? Obviously the science is pretty cut and dried. In terms of how society views people who are intelligent [but] also display non-neurotypical traits, do you think this paper could possibly change the way we perceive those who are on the spectrum?

First of all, I never told anyone I had autism. You know what my biggest barrier was in the '70s in the feedlot industry, the cattle industry, in Arizona in the '70s? Being a woman. Much bigger barrier than autism ever was. Being a woman was the biggest barrier. I got kicked out of places for being a woman.

So you're saying that's a much bigger barrier for you than being on the spectrum?

For much of my career, a much bigger barrier. Early 1970s, I want to emphasize early '70s, much bigger barrier, much bigger barrier. This is the early '70s when I started.

And the way, what I did is I had to prove to them. I had to be three times better than a guy. The thing that I got people to accept me is when I showed my work. I would lay the drawings out. I'd go in for an interview and I'd take a big drawing, lay it out on the table, put all the pictures out there that I had, pictures of jobs. I'd give them my brochure, I'd give trade magazine articles that I'd written. I just would show off the work, period. I showed the work. That was my total way of doing it and I wrote about my projects.

But if we're talking about people who do struggle because they're not neurotypical, and they tend to be intelligent but society views them

I can't talk in abstractions. I'm a visual thinker, I only think in specific examples. Then I take specific examples and I put them into categories. Very verbalized, abstract things, I can only get specific examples of all right, here's a person where they had a successful career, here's a person that did not. What could have derailed their career?

I could talk about myself. This isn't so much in terms of derailing my career, but when I tell people I'm on the autism spectrum and that I struggle with mental health issues like ADD, anxiety, depression frequently they respond by saying "Well you're so very intelligent." It seems like there is a struggle in reconciling the fact that I'm bright with the fact that I have all of these mental health issues. I know other people who are also successful in their careers who have had similar reactions.

So my question is, it seems like there's a cultural tendency to assume that if you struggle with mental health issues or you're not neurotypical, that means you're not very bright. And if you are very bright, that means you're well adjusted.

Intelligence and creativity is associated with mental health issues. I'm right now reviewing some literature on visual thinking and I'm finding papers where right now I'm looking at a bunch of journal articles I looked up online about the ability to remember your past. People who get really bad PTSD, the past just comes back like pictures. Then you've got people that are highly verbal, it's easier for them to forget that bad things have happened to them in the past. Some of those visual thinkers, they're really creative. I've worked with them on equipment design. I worked with two guys that had 20 patents each. Yeah they had problems drinking, they had some problems. They ended up both on Prozac and that basically saved them from the gutter. One still has a very successful business. I have to be very vague about what they do, I cannot identify them, they're still alive, [one] still owns a very successful business. I know he has problems with drinking. It's mechanical, very clever mechanical engineering is what he did, what he does.

That's where I was going with my earlier question. There seem to be these cultural assumptions that are not borne out by the scientific data. There is something else I want to go into, which is you're talking about the different types. In your book, you discuss the different types of autistic brains, the different manifestations

Of thinkers, different thinkers. I'm right now reviewing literature on this, recent literature. It's very clear that you've got some people, now they're not looking at mental health here, they're just looking at more career stuff. Object visualizer, that would be me. Thinks in pictures, often ends up in the arts, industrial designs. Then you have the visual-spatial, or mathematical mind, thinks in patterns. Then you have people that totally think in words. I'm right now reviewing literature right now, new literature, stuff published since 2016 after I did"The Autistic Brain", that totally supports this idea that you've got some people ... They have people that are mixtures though, the intermediate.

The person who is a super good object visualizer is going to be crappy in math, not good at math and the more spatial way of looking at things, the more mathematical way of looking at things. There's getting to be good evidence. The object visualizer and visual-spatial, the skills sort of are antagonistic. You can't be super good at both. You can be intermediate at both. But the people that are super good at object visualizing, like they are horrible at the more abstract, schematic and mathematic way of visual spatial. I'm horrible on a thing called paper fold test. I flunked that. Just last night, I took a little mechanical aptitude test that was online. I had to speed through and I got seven out of 10 right. I'm pretty sure I know which ones I got wrong.

For me personally, I've always been very good at writing and I tend to absorb a lot of information. I can read a 500-page book in a few hours and remember all of the major facts within that book months and months later. So I guess what category of intelligence would I then be in?

Let me just ask you a question. I want you to think about cell phone towers. How do they come into your mind?

I imagine a large metal tower in the middle of the woods.

Is it a specific or general?

I just imagine the concept of the tower. I don't visualize it.

Yeah, the visual thinker starts naming them off. Now I'm thinking of it, there's one I go by that's next to a gas station. It's one of their best fake trees but it's still really fake looking. As I talk about it now I see it.

Yeah, I just imagine the concept of a tower.

I take specific examples of cell phone towers. Now there's another cell phone tower, it's actually the Hilton hotel and they now have them along the edge of the roof. I see. I've also seen them used as church steeples. I'll never forget when I asked, this is when I discovered that some people didn't think visually, I asked a speech therapist at an autism conference, think about a church steeple. She just got very vague pointy thing. I see it and I start naming them off. Visual thinkers just come up, just like it showed in the movie, like PowerPoint slides.

So for me, I just think of the concept, I don't think of specifics.

Well then you're more verbal. You're probably a lot more verbal.

How would you say cultural attitudes towards non-neurotypical personality types have changed over the last 40 to 50 year?

Well it has changed. I look back on the people I worked with, welders and designer. The people who have the 20 patents, neither one of those, one barely graduated from high school and the other one I think dropped out of high school. They couldn't do math but they've got 20 patents and their stuff is out being used in the industry. They were saved by welding class. One guy he just started making stuff and selling it at local trade shows. That grew into a big business. I worked with welders, I worked with a lot of people. If I tell you of people I worked with on my projects, I'm going to guess 20 percent of them would be considered neurodiverse today. But this is long before that term ever [became popularized]. 20 percent were either autistic, dyslexic, or ADHD. There was one guy, looking at him now, he was sound sensitive. I'll never forget the job where I was chipping the slag off of his welds and me tapping with the chipping hammer drove him just crazy. I didn't realize it. This was back in 1980.

See more here:
Interview with Temple Grandin: Autism, genetics and the steep price of being intelligent - Salon

Ancestry and 23andMe offer direct-to-consumer DNA tests.(Photo: Reviewed.com/Jackson Ruckar)

It's a question that has vexed researchers from the beginning of the coronavirus outbreak: Why do some people get severely ill and die from COVID-19, while others have mild symptoms or none at all?

Now, scientists at two direct-to-consumer genealogy DNA companies hope to use the genomesthey've collected from millions of people over the years to see if they can find a genetic explanation toanswer that question.

Both 23andMe and Ancestry have launched COVID-19 studies, asking U.S. adult customers who've already submitted DNA samples to answer online questions about how the virus affected or didn't affect them.

"From the early days ... I think it was clear to all of us that some people were getting very, very sick when they were affected with coronavirus, and some people had hardly any symptoms at all," said Dr. Catherine Ball,chief scientific officer at Utah-based Ancestry."It turns out that there are plenty of people who have no symptoms. The spectrum of human response to the same pathogen is unusual.

"And even with a bunch of comorbidities and other problems, it's still remarkably divergent in different people, even if they have the same age and have the same overall health. And soto geneticists, that looks like there's a genetic factor in whether people become infected in the first placeor have serious or mild symptoms."

With 16 million people who've already spit in vials and sent them to Ancestryfor genetic testing to find blood relatives who might be closely or distantly related or learn how much of their DNA suggests their relatives came from Africa or Asia or were Native American or European, Ball said the companyknew it had a potentially useful data pool to tap for COVID-19 research.

"We clearly want to take the opportunity to unleash that power to be able to see if there are genetic signals, and be able to help researchers and people making drugs and therapeutics and vaccines dosmarter work faster," she said.

Dr. Catherine Ball, chief scientific officer for Utah-based Ancestry.(Photo: Ancestry)

Of those 16 million DNA customers through Ancestry, so far about 500,000people have already taken an online survey to participate in the company'scoronavirus research.

At 23andMe, principal scientist Adam Auton said the California-based company's COVID-19 genome-wide association study launched in April.

About 10 million of itsgenotype customers are eligible for the study, he said.Of them, about 80%have consented to participate in research, and600,000 customers have opted into the COVID-19 study.

"It is a really quite tremendous response to the study and I think shows that people really do want to try and contribute to help understand and fight this disease," said Auton.

Both Ancestry and 23andMeacknowledge that the bigger the sample size, the better their research will be.

"Never ask a scientisthow much data she needsbecause she always needs more," Ball said. "We're really hoping to get a minimum of a million respondentsbecause we need to have a decent number of people who have tested positive to give us a statistical signal."

So far, about9,000 people in 23andMe'sCOVID-19 study reported that theytested positive for coronavirus.

"That's a pretty substantial number," Auton said. "However, it's the nature of genetic studies that we really need very large numbers of people to be able to draw connections between the genetic information and people's health information."

A worker at 23andMe performs DNA testing on samples provided by customers.(Photo: 23andMe)

Since the pandemic began,about 1.6million people in the United States, a country of 330 million, have tested positive for COVID-19. As the virus continues to spread,and more people get coronavirus diagnoses, the companies suspect that the number of people who will go on to enroll in their studies also is likely to rise.

"We understand this is an evolving situation," Ball said. "And while we can't shelter in place forever, at some point, as we're opening up our cities and states, more people will start contracting the virus."

Anyone who may have already filled out anonline COVID-19 survey on Ancestry.com or 23andMe.com, saying they had not yet had the virus, can go back and revise their answers later to reflect that they've contracted it.

To expand its research of people who've had COVID-19 even more, Auton said 23andMeis now offering tomail a free DNA test kit to any U.S adult who was hospitalized with COVID-19, but has not yet submitted a DNA sample to the company.

"We are essentially asking if people have been hospitalized with COVID-19, and they have recovered, if they would like to participate inour research. They can come to our website and we'll offer them a free kit,"Auton said.

The contents of a 23andMe kit.(Photo: 23andMe)

"We're very much interested in trying to get the word out so that people to hear about this because really every data point is going to be pretty valuable."

23andMe has emailed customers in areas hardest hit so far in the pandemic including those in Michiganto let them know about its study, Auton said.

"The best thing that we can do to make a difference for COVID is to really publish the results that we find and make them available to the research and scientific communities," he said.

23andMe haspublishedmore than 150 studies in peer-reviewed scientific journals, "the majority of which come from collaboration with the broader academic and the scientific community," Auton said,since it launched in 2006with its direct-to-consumer DNA kit.

But the company ran afoul of the U.S. Food and Drug Administration in 2013, when the agency ordered 23andMeto halt the release of genetic health information to customers, saying the company had yet to prove its tests were"analytically or clinically validated."

After revamping, the company passed FDA muster in 2017, and got authorization tooffergenetic healthreports that outlinedrisk for 10conditions, including late-onset Alzheimers disease andParkinsons disease.

Ancestry is new to the health genetics business. It launched AncestryHealth in 2019, with the disclaimer that its tests are physician-ordered and not diagnostic, but offer "health insights" into whether a person might be a carrier for cystic fibrosis or sickle cell anemia or whether there's a genetic variant associated with a higher risk for breast cancer or colon cancer.

Ball said Ancestry also will seek to publish its COVID-19 research findings, too.

"We will be doing our very best to publish our findings as quickly as possible, and making them as useful to clinicians and other researchers as quickly as possible," she said.

Ancestry DNA(Photo: Melissa Rorech)

Both companies are looking for research partners for the coronavirus studies. Ancestry has had nibbles from universities, biotech and pharmaceutical companies, but Ball said, right now, the focus is on safeguarding the privacy of its customers.

"We typically do not share data out with third parties," Ball said. "That's an unusual activity for us.

"We will not be sharingpersonal data. Everything will be de-identified. So names, email addresses, your address, your ZIP code, your phone number, all that stuff will be stripped and will not be shared. We do want to still be very conservative because it is people's genetic data."

At 23andMe, individual-level data is never shared with a third party "without explicit additional consent from participants," Auton said.

"The information that we're talking about here, where we would be working with the academic community, is all aggregated at a very high level. So it's really just information about whether a specific genetic variant is associated with the disease. It doesn't contain any information about the individuals in the study."

Ball urged people to consider participating in this research for the common good.

"The people who came to AncestryDNA were interested in finding out about their ancestors, their past and their history," she said."This is our chancein this moment of history ... to take 5-10 minutes ... and do our best to help our community of friends or familyand the people who we don't even know who will be coming along later.

"It's our chance to contribute to the benefit of everybody. And I think right now, it'san opportunity that resonates with a lot of people."

Auton said the research could lead to therapies or treatments for people sickened by COVID-19.

"Hopefully, that can make a difference," he said.

Contact Kristen Jordan Shamus: 313-222-5997 or kshamus@freepress.com. Follow her on Twitter @kristenshamus.

Read or Share this story: https://www.freep.com/story/news/health/2020/05/26/genes-dna-ancestry-23-andme-coronavirus-covid-19/5223568002/

Read the original:
Genetic genealogy companies Ancestry, 23andMe begin COVID-19 research - Detroit Free Press

Researchers are learning more about genetic aberrations common in the rare but clinically aggressive hematological cancer blastic plasmacytoid dendritic cell neoplasm. There is one targeted therapy approved by the U.S. Food and Drug Administration: Elzonris (tagraxofusp-erzs, Stemline). However, more treatment options are needed to improve the cancers clinical outcome, according to a review published May 2020 in Critical Reviews Oncology/Hematology.1

Dermatologists might be the first providers to encounter patients with blastic plasmacytoid dendritic cell neoplasm because more than 70% of these patients have cutaneous lesions. Those lesions often are asymptomatic and vary in size. The skin lesions tend to have nodules, plaques or bruise-like areas, a brown to violet color and might be solitary or multifocal, according to the authors.

Blastic plasmacytoid dendritic cell neoplasm often originates from type 2 myeloid-derived resting plasmacytoid dendritic cell precursors. Recent research suggests providers can diagnose the cancer when patients express at least four of five plasmacytoid dendritic cell specific markers, CD4, CD56, CD123, TCL1 and BDCA-2, without expressing myeloid, T-cell or B-cell lineage markers.

Commonly, [blastic plasmacytoid dendritic cell neoplasm] is characterized by high CD123 expression, aberrant NF-B [nuclear factor-B] activation, dependence on TCF4-/BRD4-network, and deregulated cholesterol metabolism, they wrote.

Despite advancing knowledge about the cancer type, patients median overall survival remains at 12 to 14 months, according to the paper. Conventional treatment approaches include chemotherapy, radiotherapy and ultimately hematopoietic stem cell transplantation. The challenges with conventional therapies are while blastic plasmacytoid dendritic cell neoplasm is sensitive to some chemotherapy regimens, patient relapse is high at more than 60%. And many patients with blastic plasmacytoid dendritic cell neoplasm are too old or frail to have intensive chemotherapy or hematopoietic stem cell transplantation, according to the authors.

Recently, the most attractive agent for [blastic plasmacytoid dendritic cell neoplasm] is tagraxofusp, which is composed of the catalytic and translocation domains of diphtheria toxin (DT) fused to interleukin-3 (IL-3), the authors wrote.

Blastic plasmacytoid dendritic cell neoplasm cells overexpress interleukin-3 receptor subunit alpha (IL3RA, also called CD123). Elzonris, or tagraxofusp-erzs, is a CD123-directed cytotoxin given intravenously, which is used to treat blastic plasmacytoid dendritic cell neoplasm in adults and in pediatric patients 2 years and older.

Researchers reported in a study of 47 blastic plasmacytoid dendritic cell neoplasm patients published in 2019 in the New England Journal of Medicine that tagraxofusp led to clinical responses in untreated and relapsed patients.2 The overall response rate with tagraxofusp was 90% and the primary outcome of complete response and clinical complete response was 72% among the previously untreated patients. Overall response was 67% in the previously treated patients. Serious adverse events including capillary leak syndrome, hepatic dysfunction and thrombocytopenia were common, according to the NEJM paper.

More targeted therapies are needed to treat blastic plasmacytoid dendritic cell neoplasm, but many potential therapeutic agents are not advancing to clinical trials, according to authors of the paper in Critical Reviews Oncology/Hematology.

Common blastic plasmacytoid dendritic cell neoplasm characteristics are genetically heterogeneous and provide valuable drug targets, according to the authors.

Apart from aberrant activation of NF-B signaling pathway, which is highly dependent on TCF4- and BRD4- transcriptional networks, cholesterol metabolism deregulation and CD123 expression, defects of DNA damage repair and mitosis are new, potential common features of the cancer. Corresponding therapies might be promising, the authors wrote.

Venetoclax, anti-CD123 CAR-T, XmAb14045 and IMGN632 are in clinical trials for blastic plasmacytoid dendritic cell neoplasm. But the authors noted that bortezomib, lenalidomide, 5-aza and pralatrexate could easily be pushed to the front line of the cancers treatment.

Disclosures:

The authors report no relevant disclosures.

References:

1. Zhang X, Sun J, Yang M, Wang L, Jin J. New perspectives in genetics and targeted therapy for blastic plasmacytoid dendritic cell neoplasm. Crit Rev Oncol Hematol. 2020 May;149:102928.2. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med. 2019;380(17):1628-1637.

See the original post here:
Genetic features pave way for targeted BPDCN therapies - Dermatology Times

A month following surgery for thyroid cancer, a Hartford Hospital patients tumor grew to 10 inches. The case was presented to the hospitals tumor board, which involved 30 doctors from different specialties.

The gene mutation found to be controlling the patients tumor growth was already well-established as a driver of melanoma, the deadliest form of skin cancer, says Dr. Sope Olugbile, medical oncologist at Hartford HealthCare.Chemotherapy wouldnt work fast enough against the aggressive tumor. Tumor board members recommended a targeted therapy already treating patients with melanoma. Without that genetic information, we wouldnt have been able to come up with that therapy, he says. The treatment saved the patients life, so far. Our goal is to use more of the genetic information to drive the treatment of cancer patients.

This type of personalized care, known as precision medicine and its subset, genomic medicine, has been offered for years at world-renowned cancer-treatment hospitals such as Memorial Sloan Kettering Cancer Center in New York, Dana-Farber Cancer Institute in Boston and University of Texas MD Anderson Cancer Center in Houston. Its now the standard of care in Connecticuts Hartford HealthCare Cancer Institute, UConn Health Center in Farmington, Connecticut Childrens Medical Center in Hartford and Smilow Cancer Center at Yale New Haven Health.Cancer therapy has become precision therapy, says Dr. Roy Herbst, professor of medicinal oncology and pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital.

Dr. Roy Herbst, of Yale Cancer Center and Smilow Cancer Hospital, says that precision care is often used in cancer treatment these days.

While its most commonly used with cancer patients, precision medicine is also making inroads into other areas of health care including the treatment of some cardiac patients. Its also being studied and used on a limited basis to treat those with rare diseases. In the U.S., newborns are screened with a blood test for hearing loss and heart defects. If detected and treated early, this can prevent death and disability in some cases. For some doctors and researchers, precision medicine holds the promise of effective targeted diseases and chronic conditions, and, even more revolutionary, the chance to prevent illness before it arises. The race is on to gather as much data as possible in order to increase understanding of the connection between genes and overall health; here in Connecticut, Yales Center for Genetic Health last fall launched its Generations project to collect DNA from 100,000 volunteers (see sidebar below).

Precision medicine involves the study of human genes, called the genome. The human genome contains 23 pairs of chromosomes within all human cells, and each chromosome contains hundreds to thousands of genes. Using high-level computing and mathematics, genomics researchers analyze massive amounts of DNA-sequence data to find variations or mutations that affect health, disease or response to drugs, according to an online description by The Jackson Laboratory for Genomic Medicine in Farmington.

Researchers can sequence an entire tumor to look for markers or abnormalities that can be treated with a targeted medication that attacks that mutation, unlike traditional chemotherapy that kills healthy cells along with cancer cells, says Herbst, also associate director for translational science at the Yale School of Medicine.

These days, when Yales precision medicine tumor board meets weekly, they dont focus on where the tumor began, he says. They look at what errors occurred in the DNA of the tumor, because once they know whats driving the tumor, they can treat it.For example, lung cancer is the most common cancer in the world. When a nonsmoker gets lung cancer, doctors sequence the tumors DNA to see if it contains one of eight genes known to mutate.

Each cancer cell has about 18,000 to 20,000 genes, and there are some cancers where just one of those genes is directing the growth of the cancer, Olugbile says. We call that the driver gene. The other 17,999 are just following the lead of that driver gene, he says. That means if we tag just that one gene with the medication then we can actually shut down the growth of the entire cancer.

Traditional chemotherapy can only be given for 4-6 months because of the side effects, while targeted oral medications have very few side effects and patients remain on them for an average of two years, Olugbile says.

In the past five years, genetic testing has become standard of care for some cancers specifically colon, lung and melanoma because those types of cancers tend to have genetic mutations that have been known to respond to therapy, says Sara Patterson, manager of clinical analytics and curation at Jackson Labs, which works with UConn and Yale researchers.But targeted therapy is not a cure-all, and researchers are still a long way from using precision medicine to treat all cancer patients. Even if cancers have the same genomic change and mutation, theres no guarantee they will all respond to the same therapy, she says.Overall, precision medicine is only effective at stopping the spread of cancer in an average of 20 percent of cancer patients treated, Olugbile says, with variations by cancer. Sometimes the cancer returns because the tumor changes to resist the therapy, Patterson adds.

As doctors and researchers do more genomic sequencing, the data pool will grow and so will knowledge of what medications work most effectively against various tumor types.The more information we gather, the better well know how to treat specific patients, Patterson says.

Reimbursement from insurance companies can be a challenge. If precision treatment for a particular type of cancer hasnt been approved by the insurance industry, its difficult to get reimbursed for genomic testing, says Sue Mockus, director of product innovation and strategic commercialization at Jackson Labs.Its a catch-22. Even though a patient with pancreatic cancer could benefit from a targeted therapy, unless that patient is part of a clinical trial that would pay for the genomic testing, the patient would have to pay out of pocket, the annual cost of which can run into the hundreds of thousands of dollars. If you do have a mutation identified and your physician wants to give you the medication off label, you have to fight with the insurance company, Mockus says.

Experts have suggested a value-based approach to precision medicine, reports the International Journal of Public Health. This means policy decisions about reimbursement and investment in research and development will factor in how long patients lives are prolonged and the quality of those lives, the Journal reports.

Oncologists also offer cancer patients immunotherapy, another form of personalized medicine, Patterson says. Theyre using diagnostic tests on tumors, independent of genomic sequencing, to determine if their tumor profiles make them a good immunotherapy candidate. Immunotherapy is approved for multiple tumor types, as long as they have certain markers, she says.

Former President Jimmy Carter became cancer free after receiving radiation and immunotherapy to treat the melanoma that had spread to his brain and liver. While immunotherapy can cure cancer for some, its only effective about 20 percent of the time, Olugbile says. It varies a bit by cancer, with some cancers having a higher success rate, he adds.

Through a collaboration with Memorial Sloan Kettering, Hartford HealthCares Advanced Disease Clinic was scheduled to open this spring to give patients even more options, he says. If targeted therapies and immunotherapies dont work or are not a match for patients, doctors will look for suitable clinical trials that offer potential treatments, Olugbile says.Our goal is to create awareness on two fronts, one is among the doctors. Yes, we are available to help if patients have gone through standard of care who didnt respond, he says. Its also an option for patients who want to be treated with precision medicine closer to home. The goal is to make it available so they dont have to go to New York or Boston, he says. Its right here in Hartford and hopefully at other cancer centers over time.

From Yale, Herbst leads a clinical trial through the National Cancer Institute where he and his team are trying to match the right patient to the right drug.Every tumor is getting sequenced. Thats accelerating the field. The sequencing techniques have gotten cheaper and faster, so we can analyze them at the point of care, Herbst says. This is why clinical trials are so important. Whats a clinical trial today is standard of care tomorrow.

In a study published in the journal Science Translational Medicine, a multi-institutional research team including a Connecticut doctor developed an advanced method to analyze existing data from thousands of clinical trials, comparing which genes FDA-approved drugs work against to the genes active in pediatric brain tumor patients. This sped up the lengthy process of developing cancer drugs.

Dr. Ching Lau, head of the oncology-hematology division at Connecticut Childrens Medical Center and the pediatric oncology-hematology department at UConn School of Medicine, is accessing the World Community Grid, an IBM-funded program that allows researchers worldwide to perform tens of thousands of virtual experiments. Instead of screening thousands and thousands of compounds to try to find a potential drug, we found we could use genomics data already available and do a more systems-approach analysis to figure out the predominant pathways driving the tumor cells, Lau, professor at The Jackson Laboratory, says in an email. Then we asked if there were any existing FDA-approved drugs that could potentially modulate those pathways.

The researchers identified eight drugs that could potentially fight medulloblastoma (MB) tumors, the most common malignant brain tumor in children. One of the drugs showed an increased survival rate in mice with MB tumors, and a clinical trial is being pursued.

Personalized medicineand heart disease

Precision medicines applications have expanded beyond cancer care. At first, much heart disease research relied on a genetic analysis of whether someone was predisposed to a disease. Thanks to a growing database of patient information that is shared worldwide, researchers can mine huge data sets with hundreds of thousands of cases for patterns and abnormalities that lead to discoveries, says Beth Taylor, associate professor of kinesiology at UConn and director of exercise physiology research in cardiology at Hartford Hospital. Researchers and clinicians know that about half the people who have heart attacks dont have the typical risk factors such as high blood pressure, obesity and diabetes. To determine why physically active people with healthy diets have heart attacks, researchers are using precision medicine to comb through large studies to find small predictors, Taylor says. Often the influence of any one factor is hard to detect unless you have a big sample size, she says.

The National Institutes of Health requires grant recipients to share their data to a national registry so that researchers have access to big data, she says. (Personal information such as date of birth, name and address are removed from files used for research studies.)

When we first began to really measure genetic variations, it was believed that was going to be the big hope in treatment, Taylor says. But genes are complex and environmental factors modify genetics for multiple generations.

For the first time ever, weve got wide-scale computing ability to analyze huge data points. This can better allow us to predict disease progression and optimize treatment, she says. Many of us would say that this concept of big data is as or more important than genetic risk. Genetic risks are not the whole picture.

For the first time ever, weve got wide-scale computing ability to analyze huge data points. This can better allow us to predict disease progression and optimize treatment.

Progress with diabetes

Precision medicine is not widely used in the treatment ofdiabetesin the U.S., except when it comes to a rare form of diabetes called neonatal diabetes mellitus. While type 1 and type 2 diabetes are controlled by two or more genesand additional genetic factors,neonatal diabetes mellitus involves a single gene and develops in babies under 6 months old.

Through genetic testing of babies with elevated blood sugar levels,researchers learnedthat about half the patients have gene mutations that respond well to a pill used to treat type 2 diabetes and they dont need to be on insulin for the rest of their lives like type 1 diabetics, says Karel Erion,director of research stewardship and communications for the American Diabetes Association.

When infants show signs of type 1 diabetes at Yale New Haven Childrens Hospital or Connecticut Childrens Medical Center, they are automatically tested for neonatal diabetes, hospital doctors say.

An example of precision medicine as a predictor of disease is the TrialNet database, which uses genetic testing to determine whether the relatives of those with type 1 diabetes have two or more of the five diabetes-related autoantibodies (proteins produced by the immune system directed against the persons own proteins) linked to increased risk of developing type 1 diabetes. Type 1 diabetics must take insulin for the rest of their lives to survive, and theres no known way to prevent the autoimmune disease. Type 1 diabetes, formerly called juvenile diabetes, typically strikes children and adolescents, causing the pancreas to stop producing insulin, a hormone needed to process sugar, or glucose, from food. Type 2 diabetes was formerly known as adult-onset diabetes, but the disorder is being seen in more children, thought to be the result of a rise in childhood obesity. Screening identifies the early stages of the disease years before any symptoms appear, according to the TrialNet website.

In a study published in the New England Journal of Medicine, researchers from the TrialNet Study Group, led by Yale Universitys Dr. Kevan Herold, found that an experimental medication delayed the onset of type 1 diabetes in high-risk participants by two years compared to the control group. The disease was diagnosed in 43 percent of the participants who received the medication, teplizumab, and 72 percent of those who received the placebo.

Alzheimers disease and dementia

Only 1 to 3 percent of the 5 million people living with Alzheimers disease have a genetic mutation that leads to whats called genetic or familial Alzheimers. But one in three older adults will eventually develop some form of dementia, says Rebecca Edelmayer, the Alzheimers Association director of scientific engagement.

Like other diseases that strike large segments of the population, researchers rely on big data to learn about Alzheimers and which genes play a role in who gets it.Researchers have learned that there are several risk factors that contribute to dementia, she says. Specifically, the presence of heart disease, high blood pressure, diabetes, social and cognitive isolation, poor nutrition and the level of education, can contribute to cognitive decline, she says.

Scientists from around the world share research data and draw from data in the Global Alzheimers Association Interactive Network, she says.The field has made some dramatic advances in understanding of how genetics play a role and how other underlying diseases play a role, Edelmayer says. We need to give doctors evidence-based recommendations.

Read the original here:
For cancer treatment and more, genetic-based precision medicine holds a lot of promise - Connecticut Magazine