Author Archives: laurahercher

by | June 6, 2023 · 9:33 AM

Eulogy for a clinic

by Jehannine Austin

My professional life up till this point has been centered around a mission to bring genetic counseling to people who – like me – live with psychiatric conditions, and their families. This has been my mission for >20 years, since my family started asking me about whether psychiatric conditions were genetic and what this meant for us while I was doing my PhD on this topic. Realizing that it wasn’t just my family that had these questions and that no-one was really addressing them is what drove me to train as a genetic counselor. Once I completed my genetic counseling training in 2003, no one would hire me to provide genetic counseling for families with psychiatric conditions. Of course, psychiatric conditions have always been profoundly disenfranchised in terms of health services, but as well, there was no evidence that people with psychiatric conditions wanted genetic counseling, and no evidence that it could help. So, this drove me into research. 

I landed a research professorship and my team and I generated data showing that: 

  1. people with psychiatric conditions wanted access to genetic counseling 
  2. genetic counseling helps people with psychiatric conditions 

In 2012, on the strength of these data, we established the Adapt clinic – the world’s first specialist psychiatric genetic counseling clinic. It was all about helping people understand the factors that contribute to developing a psychiatric condition, and how to use this understanding to engage in self-management strategies to protect their mental health for the future. It was about helping people to make meaning, and understand that psychiatric illness is not your fault, and not your fate. 

In 2023, after 11 years of helping patients, training students, generating research data about the impact of what we do, and providing a model for psychiatric genetic counseling services around the world, our service is being closed.

I’ve fought this with everything I have because it feels so wrong. But I’m so bone tired …and there’s literally nothing more I can do. It’s over.

No amount of data demonstrating the awesome outcomes that patients experience (increases in empowerment, changes in behavior to engage in self-management strategies to protect their mental health) after receiving our services has swayed the decision. So, this is a eulogy.

The webpage for the clinic has silently ceased to exist. 

The reason given for the death of the Adapt clinic? To redeploy the counselors to provide service for general genetics patients because the waitlist there is so long. It’s apparently that simple. And pointing out that this is classic disenfranchisement of people with psychiatric conditions – again, people like me – has made no impact. I may as well be speaking to a wall. 

Now, as someone who has served as a leader myself in a publicly funded healthcare setting, I do of course understand that we are forced to make decisions about how to allocate scant resources. And sometimes people might not like the choices we make. I understand that. My objection is that the Adapt clinic embodies (has embodied) all of the principles and values claimed to be held dear by the healthcare system that is closing it. That is what I find distressing.

Initially, when I saw the writing on the wall that the clinic would be closed, I was devastated- this was my life’s work, I thought. And it’s been for nothing, my internal voice said…I am a failure. I lost all energy to continue in my efforts to leave things better in the world than I had found them. Because, what is the point? I – and the counselors within it – gave the Adapt clinic everything we had, it was demonstrably successful, and yet it is still being closed….it felt like it was all for nothing.

But this narrative is wrong. I can see that I am not a failure, and that the clinic was not a failure. Instead, the clinic, and the counselors within it, and the patients we serve, have all been failed by the system we are in. 

Our efforts were not for nothing. The Adapt clinic has helped about 1400 patients and trained over 50 students, some focused on clinical skills, some focused on research skills, and some both. We published about 20 papers that are out there in the world that explain the difference that psychiatric genetic counseling can make for people, and how to do it well. I know that we have inspired practicing genetic counselors around the world as well as students…we have inspired people to train in this discipline. I know this because people have been gracious enough to tell me about how our work has affected them.

Given all this, you have to ask, why is the clinic dead?  I think there are two real answers to that. First, psychiatric conditions are still so stigmatized. People with mental illness – like me – have a long and awful history of being disenfranchised, and here we see it again: an evidence-based service for people with psychiatric conditions cut, despite data showing that it’s needed and it helps. And yet it’s cut so that we can prioritize providing services for people with non-psychiatric indications. 

Second, the genetic counseling services we provide for people with psychiatric conditions typically don’t involve genetic testing. And though the service helps people, the health system decision-makers don’t value genetic counseling when there’s no genetic testing being done. The psychotherapeutic work we do is not valued …which is truly the hardest thing for me to swallow, because data show that it’s exactly this that makes the difference even when genetic testing *is* available. It’s the counseling that helps people. 

So, yes, this is a eulogy — a public expression of pain and grief and disillusionment about the death of a clinic whose establishment was the culmination of >10 years of my work, that we nurtured successfully for 11 years, and that brought purpose to my life and a way to channel my own experience of psychiatric illness to help others. It’s so hard to build and create something new and innovative, and so very easy to destroy it. It does feel like a death. 

My biggest fear is that others will stop trying to establish psychiatric genetic counseling clinics in other jurisdictions as a result of this. People – like me- who have psychiatric conditions deserve better than this. So please keep pushing. Others have taken up the mantle – there’s a clinic in Cardiff, and Tennessee, and others (if you know of others, please tell me!)… I’m rooting for all of you. Please let me know how I can help. 

But I think this reflects broader issues too – I think as a profession, we have to answer some questions for ourselves. Are we happy with being reduced to roles as the purveyors of genetic testing? And only post-test counseling at that? This is the direction in which we are headed. Medical genetics departments with long and growing waitlists often respond by simply reducing the list of indications to make fewer people eligible to access genetics services.  That’s exactly what happened to the Adapt clinic — the eligibility criteria for access to genetics services shrank to exclude our patients. What happens to these patients? It’s not that they get service elsewhere – they don’t. The people who make these decisions are deciding who gets care — deciding who matters. This is an issue that relates to equity and justice. 

In writing this eulogy for the clinic that I created and loved, my purpose is to try to use its death for something positive. Given our increasing focus on the importance of EDI issues, I would like to suggest that this is an opportunity to question whether tertiary-care clinical genetics is the right location for genetic counselors if we are to be able to provide just and equitable access to our services for people who need them. Situating genetic counseling services in alternative locations, such as primary care/family practice, might be worth considering as a way to ensure our ability to practice to the top of our scope, to offer more than just genetic testing (like psychiatric genetic counseling), and to ensure more equitable access for patients. 

I hope that the end of Adapt can be used as an impetus for the start of something new. If the Adapt clinic has impacted you in some way, those of us who nurtured it would love to hear about it in the replies, or by message. 

Some of my fave quotes from people who had psychiatric genetic counseling in the Adapt clinic (from Semaka et al 2019):

“Until genetic counseling, no one ever coherently explained to me why I have a mental illness. And I think that’s a conversation that needs to be had because most people just think they’re having a bad time of it or they just think that they just need to try harder”

“I felt in control, you know [psychiatric genetic counseling] made me feel more empowered than I did when I walked in and I think for me that’s a big deal… I just felt after the appointment I had more tools to control my life.”

“[Psychiatric genetic counseling] gets rid of some of the shame…. with mental illness, it’s so hard to know what you did wrong but really you didn’t do anything wrong and [psychiatric genetic counseling] just explains that to you… so you’re able to look at this and think, ‘OK, this isn’t my fault’”. 

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by | September 16, 2022 · 5:08 PM

GUEST POST: The NSGC Annual Conference needs a high-grade mask mandate

by a collective of GCs concerned about COVID-19 risk at the 2022 AC

We urge the NSGC Board of Directors to change the mask recommendation for the 2022 Annual Conference (AC) to a requirement for attendees to wear high grade masks (N95, KN95, surgical). 

We encourage our fellow genetic counselors to join us in advocating for high-grade masks at the AC by signing this petition and sharing it with their colleagues. 

Below we share examples from recent conferences to demonstrate that without a masking requirement, the AC is likely to be a superspreader event and that masking requirements are indeed feasible at conferences of this type and size. We also lay out why this policy change is imperative given NSGC’s stated J.E.D.I. commitments and our profession’s responsibility to our attendees (including vendors, exhibitors, facility workers, and the press), patients, colleagues, families, the local community of Nashville, and society broadly. 

Likelihood of high level of COVID-19 transmission at events like the AC

Unfortunately, even in 2022, conferences without masks continue to be superspreader events. The Society for Academic Emergency Medicine Conference had an estimated 18-67% of its ~3000 attendees contract COVID-19 at their May 2022 conference. This conference required vaccination but not masks. A July 2022 meeting of IT developers had at least 50% of attendees test positive for COVID-19 after the conference. That meeting required both vaccination and pre-conference testing, but not masking (same as the policies proposed for the 2022 AC). This example shows that transmission rates can still be high even with the policies proposed for the AC. 

In contrast, the 2022 Academic Surgical Congress required high-grade masks (N95, KN95, surgical) and far fewer attendees contracted COVID-19. In a recent paper Silver et al. (2022) report that 1.8% of in-person attendees at this conference tested positive for COVID-19 after the meeting, a rate that is both markedly lower than the unmasked conferences mentioned above and similar to the rate among remote attendees (1.5%). It is notable that this paper came out after the Board made decisions about AC policies, which further prompts the need for re-assessment of those policies. 

NSGC staff have shared that they hope that attendees will heed the recommendation to wear masks. However, rates of masking at conferences with a recommendation as opposed to a requirement suggest that many will not, as does an informal poll in which 30% of respondents who plan to attend the AC in person said they would not wear a mask under the currently proposed policies. 

Feasibility of mask mandates

It is notable that many recent in-person medical conferences have required masks and had a high rate of masking compliance. This suggests that a mask mandate is indeed feasible and also that masking rates are higher with a mandate than a recommendation. In addition to the Academic Surgical Congress discussed above,the Heart Rhythm Society and American Academy of Neurology 2022 meetings are notable examples. Both required masking. Genetic counselors who attended these meetings report that compliance was very high and that security guards and conference staff provided cordial reminders to mask when they were already interacting with attendees, such as at entry points. This suggests that a high rate of masking can be achieved when a mask mandate is coupled with a minimal level of additional work from existing conference staff. Further, the Heart Rhythm Society registration page informed potential attendees in advance of requirements, including mandatory masking, and asked that individuals who could not meet those requirements attend remotely. Within the genetic counseling profession, the Southern California Genetic Counselors’ 2022 conference is an example of another recent meeting that required masking and had very high compliance. If these societies were able to implement a mask mandate and achieve a high level of compliance, then so can NSGC. 

Lastly, many upcoming conferences are requiring masks, most notably this includes the American Public Health Association Annual Meeting. 

J.E.D.I.

NSGC has made significant strides in recent years in recognizing the need for greater equity and inclusion within the society. However, opting for a mask recommendation over a mask mandate is counter to the society’s stated J.E.D.I. goals. Specifically, by not including this feasible and highly effective mitigation strategy, NSGC has rendered in-person attendance at the AC out of reach to attendees who are at high risk for COVID-19 complications, or who live with someone who is. This policy choice disproportionately harms disabled individuals. In-person attendance at the AC offers many more choices for educational talks and provides access to additional networking opportunities, pre-conference symposia, and sponsored sessions. In the same informal poll referenced above, 11.5% stated they would change from remote to in-person attendance if masks were required. 

Our collective responsibility

As both a professional society and a collective of healthcare providers and individuals, we have a responsibility to minimize the risk of transmission at our Annual Conference. So much so that one group of experts titled their article on this topic “The irony — and ignominy — of medical conferences as superspreader events.” To abide by our duties as healthcare providers and our responsibilities to our patients, we must do whatever we can to save lives and prevent long COVID-related disability by minimizing the number of attendees who bring COVID-19 home to their families, communities, clinics, and workplaces. Not taking that step would be against the values of care and respect for our patients’ welfare that are the foundation of our Code of Ethics. 

Clearer communication of rationale for policy choices and risks to attendees

Lastly, we urge the Board to provide clearer communication on COVID-19 policies for the AC, even if they do not adopt a mask mandate. Communication from NSGC to date does not provide a rationale for the chosen policies or clarity on the process for selecting those policies, nor does it communicate where the current policies may cause significant risk to attendees. The risk of attending should not be left to attendees to discern. As a profession that facilitates and is committed to informed choice, we owe it to each other to help provide accurate and up-to-date information on the risks of conference attendance, especially given that such information is not readily provided from sources most attendees would encounter. 

Signees

Colleen Caleshu

Brenden Phung

Sohnee Ahmed

Kaleigh Patton

Emma Snyder

Gina Sanchez

Breanne Prindeville

Sarina Kopinsky

Samantha Freeze

Charlene Preys

Emily Toering

Sally Rodriguez

Naomi Wagner

Meg Hager

Michelle Takemoto

Suzy Cahn

Ariel Breeze

Vickie Bacon

Julia Stone

Liz Mizerik

Natasha Berman

Catriona Hippman

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by | July 28, 2022 · 7:47 AM

NSGC Board: With Roe Overturned, and Over a Decade Without Medicare Recognition, It’s Time For Change 

A Guest Post by Misha Rashkin et al

The Supreme Court’s recent decision to overturn Roe v. Wade is an historic event, and in many ways genetic counselors are in the eye of the storm. The National Society of Genetic Counselors (NSGC) has historically remained silent on the issue of reproductive rights, citing Medicare recognition as a bipartisan issue that supersedes patients’ reproductive freedom. Though the threat of losing Roe has been clear since Brett Kavanaugh joined the Supreme Court, and all but inevitable after Justice Coney Barrett took the oath, NSGC leadership has continued to focus solely on Medicare reimbursement. After more than a decade of following this strategy, NSGC is nowhere near getting our bill passed, and now patients are losing fundamental rights. It’s time for change.

What is Next for Genetic Counselors?

  • Going forward, there will be laws proposed in many states that could regulate what genetic counselors can document or say to their patients. 
  • To enact change, NSGC leadership will need to get involved in many legislative, legal, and electoral efforts. 
  • Electoral efforts will need to focus on local elected officials like District Attorneys offices, ballot measures, and state constitutional amendments. 

Bottom line: It is not acceptable for NSGCs political operation to remain silent on reproductive choice. We must act on issues that impact our professional lives and the wellbeing of our patients. To remain silent is to capitulate.

What about our bill to be recognized by Medicare? 

  • Based on public records, NSGCs efforts to have Congress recognize genetic counselors as Medicare providers has been ongoing since 2007, longer than many counselors’ careers. 
  • Our bill has been introduced three times as HR 7083 in 2018, HR 3235 in 2019, and HR 2144 in 2021, and has yet to be considered by a single committee in Congress. 
  • While progress has been minimal, costs have ballooned 450% over 10 years, from $80,000 per year to $360,000 per year! 

Bottom line: Sacrificing our commitment to patient autonomy and agency is a grave ethical error for an industry that prioritizes these values. Sticking with the status quo is a failure of the leadership’s ethical and fiduciary responsibility. Board members are required to accept their fiduciary responsibility for NSGC the same as they would for their own personal finances.

What Can NSGC Do To Repair the Damage?

  • The NSGC Board should put out a Request For Proposals (RFP) requesting bids from new lobbying firms every few years, beginning now. This is standard practice for nonprofit organizations. Smith Bucklin has not been held accountable for their lack of progress. 
  • RFPs should include lobbyists who have worked to get mid-level providers recognition.
  • This process should be transparent and prioritize bids from political operatives who have:
    • Experience working with our targeted committees (Energy & Commerce, and Ways & Means in the US House) to move our legislation forward.
    • Experience working on reproductive freedom at the state and federal level. 

Bottom Line: The Board should create a process where an RFP is put out at some regular cadence, such as every three years. It’s time to hold our Director of Government Relations and lobbyists accountable. If you agree, please sign this petition to register your support for accountability, transparency and change. 

[alphabetical order]

Barbara Biesecker, PhD, MS, CGC

1989-1990 NSGC President

Jordan Brown MA, MS, CGC

2022 Chair, NSGC Public Policy Committee

Member, NSGC Reproductive Freedom, Access, and Justice Task Force

Founding Member, Genuine Collective

Elizabeth Fieg, MS, CGC

2020-2022, Public Policy Committee Member

Michelle Fox, MS, CGC

2020-2021, NSGC Director at Large

2008 Chair, Jane Engelberg Memorial Fellowship 

Shreshtha Garg, MS, CGC
2020-2021 Chair, Equity and Inclusion Implementation Committee

Carrie Haverty, MS, CGC

2022 Chair, NSGC Membership Committee

Brianne Kirkpatrick, MS, CGC

204-2017, NSGC Public Policy Committee Member

Shelby Koenig, MS, CGC

Member, NSGC Reproductive Freedom, Access, and Justice Task Force

Megan Mckenna, MS, CGC

NSGC Member since 2020

Kristen Miller, MGC, CGC

2022 Senior Co-Chair, NSGC Prenatal SIG

Ana Morales, MS, CGC

2016-2020, ABGC Board of Directors (President, 2019)

2022, NSGC Expert Media Panel

2022, NSGC Practice Guidelines Committee Member 

Shivani Nazareth, MS, CGC

2020-2021, NSGC Director at Large

2021-2022, NSGC Reproductive Freedom, Access and Justice Task Force Member

2013-2016, Public Policy Committee Member

Kate Partynski Emery, MS, CGC

NSGC Member Since 2015

Aarti Ramdaney, MS, CGC

2019-2021, NSGC Prenatal SIG Co-Chair

Misha Rashkin, MS, CGC

2018 Chair, NSGC Public Policy Committee

Hillary Rieger, MA, MS, CGC

NSGC JEDI Task Force, 2021-22 

Sally A. Rodríguez, ScM, CGC

2021-2023, NSGC Membership Committee Member

2021-2023, NSGC Justice, Equity, Diversity, & Inclusion (J.E.D.I.) Committee Member

Katie Sagaser, MS, LCGC

2020-2022 NSGC Public Policy Committee Member

2019-2020 NSGC Prenatal SIG Co-Chair

Founding Member, GENUINE Collective

Kendra Schaa, ScM, CGC

2020-2021, Chair, NSGC Access & Service Delivery Committee

2017-2020, Member, NSGC Access & Service Delivery Committee

Heather Shappell, MS, CGC

2020-2021, NSGC Director at Large

Ashley Svenson, MS, CGC

2021-2022, NSGC Reproductive Freedom, Access, and Justice Task Force Member

Elizabeth Varga, MS, CGC

2018-2019 NSGC Director at Large

2016-2017 Co-chair, Pediatric Subcommittee, Cancer SIG

2014 Chair, Nominating Committee, American Board of Genetic Counseling

Chelsea Wagner, MS, CGC

2022-Present, Prenatal SIG Co-Chair

2022-Present, NSGC Abstract Review Committee

2019-2021, NSGC Marketing and Communications Working Group

2017-2020, NSGC Membership Committee

Kate L Wilson, MS CGC

2014 Chair, NSGC Access and Service Delivery Committee

2018 Chair, NSGC Education Committee

2012 Chair, NSGC Prenatal SIG

2017 Chair, NSGC Laboratory/Industry SIG

Beth Wood Denne, MS, CGC

2019 NSGC Cares Task Force

2011 Chair, Annual Education Conference

2013-2016, ABGC Board of Directors (President, 2016)

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by | September 21, 2020 · 9:39 AM

JOAN H. MARKS 

In Memoriam

1929-2020

Of all the pioneers who helped shape the field of genetic counseling, it is likely that no one was more influential than Joan H. Marks, who died on September 14th at the age of 91.  In 1972, when Joan took over the 3-year-old program at Sarah Lawrence College that now bears her name, there was no accrediting body, no national society, no Journal of Genetic Counseling.  She stayed for 26 years, a dominating and charismatic presence, often intimidating, often demanding – a fierce advocate for both genetic counselors and their patients, who she insisted deserved more than a lecture on chromosomes and recessive inheritance.  

When your friends and relatives ask you, as they still do, ‘what is a genetic counselor?’ the answer you provide, whether you know it or not, is an echo of Joan’s vision, distilled in a generation of students who went on to define their roles in workplaces across the country, to found NSGC and ABGC, and to serve as teachers and program directors in their turn, passing along the ethos that remains integral to the field.  

I met Joan when I interviewed at Sarah Lawrence in 1999, when she was very much the eminence grise.  “I imagine you’ll get in,” she said to me, looking over my transcript with a practiced air, and I was thrilled – an excitement that was immediately tempered when she mentioned that she would not be sticking around to educate this new class of genetic counselors.  As a charter member of the post-Joan-Marks generation of Sarah Lawrence alums, I can attest to the lingering effects of her legacy.  

Still, devoted former students have told me over the years that I was unlucky not to have known her better.  No doubt this is true (and no offense to Caroline Lieber, who inherited the mantle at Sarah Lawrence and was a great program director in her own right).  So today I would like to invite all of you who knew Joan Marks as a student or a colleague or a friend to treat this post as a sort of an invitation and add your reminiscences here.  

First up, a lovely tribute form Caroline Lieber herself, who talks about her experience filling some very big shoes in the world of genetic counseling.  I hope that many others will fill the comments.

Joan Marks: One of a kind

Caroline Lieber, MS, CGC Director Emeritus, Sarah Lawrence College Joan H Marks Graduate Program in Human Genetics

I met Joan Marks in February 1978.  My then-boyfriend and I flew to New York and then took the train to the Sarah Lawrence campus, two California kids in New York for the first time.  He waited outside of Morrill House while she and I “talked.”  It felt more like she talked and I listened.  After the interview I said, “I am not sure that went so well….” 

But when I called my parents from South America that July to check-in, my father excitedly said, “You got accepted at Sarah Lawrence!” My boyfriend and I packed our meager belongings and headed east. Two California kids in New York for the second time. We arrived two weeks before classes were scheduled to start.  I was going to be a genetic counselor!

Having been undergraduate genetics major, I was comfortable in the science courses. The psychology courses were a different story.  As our instructor for “Issues in Genetic Counseling,” Joan had us read broadly about ethical concerns, the depth of emotional responses to genetic conditions in families, and articles to help identify counseling techniques and how to use them.  She commented in detail on each paper we wrote.  In one paper I found recently, she pointed out some inconsistencies in my thinking.  She further remarked, “But what’s good is that you see yourself as a counselor and you see how tough it can be. I’d like you to reread what you’ve written carefully and try to be objective-aren’t you inserting some biases here and there?” Her critique was not always welcome, but she always made me reflect on each point she made, and to look at it from another view.  I learned to be more empathic in a tough-love way. I am proud of the genetic counselor I became under her direction.

Fast forward to 1998. I discovered that Joan was planning to retire from Sarah Lawrence. I applied for the director position, and went through rigorous interviews.  I recall the pointed questions, some designed to make the interviewee a bit uncomfortable, as a means of gauging responses to tough situations. Even though she wasn’t in the room, it was clear that Joan was part of the process. Fortunately for me, I was selected.

Following in Joan’s footsteps was daunting.  Those early months felt exciting and overwhelming as I learned a whole new landscape.  Not surprisingly, Joan had very definitive ideas about the future of the program and often wanted to share her thoughts.  As my advisor and mentor, I made a point of responding to her calls and emails, listening to her guidance and counsel.  As it was when I was a student, I was not always in sync with her thoughts, but I learned to incorporate many of her suggestions. As I gained confidence in my role, I learned to trust my instincts and experiences to find my own personality in the position.  When in time, Joan told me that I was doing a good job, letting me know that she approved of my leadership, it meant a great deal to me.

During my tenure as program director, our relationship grew on many levels.  Joan and I grew together professionally as we worked on several commemorative events. When the program was renamed in Joan’s honor, it was a proud day for the college and the Joan H Marks Graduate Program in Human Genetics.  After I moved into New York City, we grew closer personally, sharing life outside of the program.  We met for lunch and talked about some of her other interests, including art and gardening. I got to know her softer side.

Joan Marks was the most committed and passionate advocate for the genetic counseling field that I have ever known.  As Laura Hercher said, “I doubt any other single individual did as much to shape the field.”  She put the profession on the map with style, charm, directness and savvy.  It was my privilege to be her student and mentee.  It was my pleasure to be her friend.

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by | December 26, 2019 · 10:45 AM

The List Returns: My Top 10 Stories in Genetics in 2019

2019!!  I’m going to declare it The Year of the Phoenix, with old promises rising from the dead (gene therapy) along with left-for-dead approaches (you came back with a vengeance, polygenic risk scores) and even older fears (remember when we were a post-racial civilization and genetic discrimination –  whew! – didn’t happen?).

Writing about 2019 got me thinking about the end of a decade, and so this year I am offering an end-of-the-decade special: two lists in one.  Here’s my take on the top ten stories in genetics for the 2000-teens (in no particular order):

Clinical use of exome sequencing

The rise of mega-databases

The ancestry-testing craze and the death of genetic privacy

Data sharing becomes the norm (kumbaya awards to gnomAD; ClinVar)

Nanopores! And other forms of heterogeneity in the F2 generation of DNA sequencing

Cell free DNA testing

Polygenic risk scores 2.0

NGS rewrites laws of economics by getting cheaper & better despite Illumina monopoly

Gene therapy rebounds

CRISPR

No surprise, many of these larger trends are reflected in the Top Ten for 2019:

 

  1. DTC: THE TRAIN HAS LEFT THE STATION BUT NOBODY KNOWS WHERE WE ARE HEADED

Can’t talk about genetics in 2019 without a word about DTC testing, as we persist in calling it for lack of a better word (consumer-initiated testing?  Not a better word, though possibly a better phrase…).  The thing is – wait for the irony – you can’t generalize about DTC anymore.  So what’s the biggest DTC story of the year?  I’m going with Ancestry branching out into the health and trait testing business.  This can hardly rate as a giant surprise, as they have hinted at it for years, but the big question was whether or not they would go with a 23andMe Fun Facts approach or something more medical.  Would they try and compete with Invitae or Color and offer a more comprehensive and more expensive CONSUMER-INITIATED, DOCTOR-APPROVED testing?  Seems like this choice would say something about where they see the field going…

And the answer was (drum roll): both.  Take your pick.  This actually does say something about the future, which is to say, we have no idea where the field is headed.  Their two-tiered approach debuts in 2020 and I expect it is more beta testing than market strategy.  I predict they are down to a single product by the time we (please God) inaugurate a new president in 2021.

 

  1. MILASEN

There are so many stories about the success of new treatments in 2019, that it was hard to pick just one.  Trikafta, the new CF combination therapy that will extend effective treatment to over 90% of the cystic fibrosis population?  Studiessuggesting the PCSK9 inhibitor inclisiran may offer a new option for individuals with a genetic predisposition to high cholesterol?

But with all these big stories to talk about, I’m going small: the development of a drug to treat a single individual, reported in October by the New York Times.  This n-of-1 drug was developed for Mila Makovec, a Colorado 8-year-old with an atypical form of Batten’s disease.  The drug, named Milasen, has improved but not cured the little girl, who has gone from 30 seizures a day to something less than 6 on average.  This example of highly personalized medicine was enabled by DNA testing, but also by the 3 million+ dollars Mila’s mother raised via a GoFundMe campaign.  Additionally, as the article points out, the nature of a custom drug is a challenge for regulators, who cannot use data to establish effectiveness or risks associated with treatment.  And without means to get FDA approval, these drugs will operate indefinitely in self-pay mode.

 

  1. FLORIDA MAN AND ACCIDENTAL PHILOSOPHER SELLS BUSINESS AND RETIRES FROM UNPAID ROLE AS ARBITER OF FORENSIC DNA USE BY AMERICAN LAW ENFORCEMENT

In 2010, retired businessman Curtis Rogers and his friend John Olsen founded GEDmatch, a website providing a set of tools to help adoptees find biological relatives.  “Premium members” paid $10 a month, most of which went to offset the cost of servers.  More of a hobby than a business, GEDmatch was staffed by volunteers.

Eight years later, Rogers described himself as shocked and surprised to discover via news reports that his site had been used by law enforcement to locate a suspected serial killer named Joseph DeAngelo, later convicted of a rape/homicide in 1977.  “It took a couple of weeks for me to really wrap my head around what was happening,” said Rogers.  GEDmatch, which was not a testing service like Ancestry or 23andMe, accepted DNA from a variety of sources, making it accessible to profiles derived from crime scene samples, and its DIY set of tools for finding relatives was tailor-made for the new field of forensic genealogy.

Did people who uploaded their DNA for genealogical purposes intend for it to be used by law enforcement?  And did their intentions matter?  Accidentally, this Florida man found himself the arbiters of forensic DNA use in the U.S.  How did he do?  Not bad, considering.  In the wake of the initial Golden State Killer hubbub, Rogers informed law enforcement that they could use GEDmatch only for crimes that included murder or sexual assault.

Then in December 2018, Rogers bent the rules to allow a search for an assault he described as “as close to a homicide as you can get” (an elderly woman playing the organ in church was choked and beaten).  This exception provoked a significant negative reaction from the GEDmatch user community, which in turn caused Rogers to rethink his approach, and in May he announced a new “opt-in” policy, restricting the police searches to those profiles whose users had provided consent.  Overnight, the new policy shrunk law enforcement’s access to GEDmatch to a meaningless fraction of the total database.  While responsive and thoughtful, this sudden about-face illustrated how much the forensic use of genealogical data rested entirely upon the decision-making of one many with no particular expertise and some conflict of interest (Rogers also mused allowed at one point that he might start charging law enforcement to use the site because, why not???).

This status quo held only briefly, with several latte-year events altering the forensic DNA landscape.  In September, the U.S. Department of Justice released interim guidelines for law enforcement that permits them to use DNA databases only for violent crimes like rape and murder, or to identify human remains, and only when traditional investigatory efforts have come up empty.  Two months later, a GEDmatch search occurred for the first time by court order, after a Florida court issued a subpoena.  And in December, Rogers sold the company and his de facto control of forensic DNA use in the U.S. to Virogen, a sequencing company specializing in forensic use of DNA.  Virogen claims it will maintain the opt-in standards set by Rogers even though those standards complicate its core business.  Anyone who takes that promise at face value should contact me; I have a bridge you might be interested in buying.

 

  1. ASCENSION HEALTH PATIENTS, MEET OUR NEW ASSOCIATE, DR. GOOGLE

Maybe they should have called it Project Canary in the Coal Mine.

Ascension Health’s Project Nightingale struck a nerve this November, when the Wall Street Journal reported that they had hired (or, in HIPPA-compliant terms, entered into partnership with..) Google to collect and analyze identifiable health data from the electronic medical records of their patients.  HIPAA forbids the sharing of a patient’s medical information without express consent, but allows for access within a medical system if it is used to improve patient services.  While Google denied any intention to use the data for other purposes or to link it with Google subsidiaries such as Calico (a partner with Ancestry, the largest of the consumer genealogy databases), many skeptical observers pointed out that health data is a valuable commodity in which Google has a previously expressed interest.

Sans accusation, it is fair to say that Project Nightingale raises legitimate concerns about the adequacy of existing privacy regulations in an age when the quantity and richness of data accessible through large health system EMR’s and genomic databases is unprecedented, and there are players like Google potentially capable of connecting the dots between genomic and health outcome data to draw conclusions about individuals and families.  It is unlikely that the architects of HIPAA envisioned the size and scope of Ascension Health (78 hospitals and over 2600 ‘points of care’ according to… Google) and there is no way that HIPAA rules governing internal partnerships were designed with Google in mind.  What could happen?  I don’t know, and neither do you, and that is actually the point.

 

  1. INVITAE INVESTS IN CHATBOTS

If you attended a genetic counseling conference this year, you likely heard a great deal about chatbots, even before reports in November of Invitae’s plans to purchase chatbot pioneer Clear Genomics for $50 million dollars (drinks on you, Shivani Nazareth!!!).  The move represents a clear (no pun intended) double down on Invitae’s other significant 2019 initiative: expanding into the world of consumer-initiated testing.  Chatbots, in this story, play the role of support staff, allowing us to triage questions and concerns that require genetic counseling from those that do not, a crucial step in expanding the use of genetic testing or screening without sacrificing our commitment to informed decision-making and responsible return of results.  In fact, relieved of menial question-answering, the GC staff are able to take more time with those who need it, and practice the sort of personalized and therapeutic relationship-building that characterizes genetic counseling at its best.

Do you sense a *but* coming?  I sense a *but* coming.

But… I have to say that while I buy the potential of chatbots for this purpose, my own view of the future is a bit of a choose-your-adventure story with alternate endings.  In the darker version, institutions and insurers decide, once the automated information-givers are in place, that this system is not intended to enable genetic counseling but to replace it.  So, yes, let’s embrace GC-Siri, but at the same time, let’s double down on producing data to support the value of the (human to human) genetic counseling experience.

 

  1. DATA SHARING HITS A MILESTONE

The clinical value of genomics is based not just on our power to sequence, but on our ability to interpret the variant calls, and for improving interpretation, there is no resource more powerful than past experience – an early-days problem for the nascent field of genomics.  ClinVar, the government-funded repository of variant calls, was developed to provide a way to maximize the value of our collective experience of the relationship between genotype and phenotype.  A real-life exercise in game theory, ClinVar represented an act of trust: hand over your work for the common good and, if enough people participate, everyone will benefit.

The result?  In December 2019, ClinVar announced that the number of shared records has passed one million.  Routinely consulted by clinicians and researchers, ClinVar has become an invaluable resource to the world.  Congrats and thanks to the thousands of volunteers who have organized data, searched records, curated variant calls and worked to promote the gospel of data sharing.

And by the way an example of government doing what private industry cannot, in the service of the public good.

 

  1. CRISPR PRIME PROMISES TO A CURE FOR YOUR GENETIC DISEASE DELIVERED IN TWO DAYS OR LESS

A novel CRISPR technique, reported in an October article in Nature, uses reverse transcriptase to introduce a desired transcript into a DNA strand, without the messiness and unpredictability of CRISPR’s double-stranded breaks.  The technique was widely hailed as a way of improving reliability of the ‘replace’ aspect of CRISPR as a ‘search and replace’ function for DNA.  And called CRISPR prime, so I guess they will give me my money back if it isn’t delivered to the right chromosome in two business days (this joke has fallen flat multiple times but I believe in it and I have the courage of my convictions).

Will CRISPR prime be transformational?  Despite the excitement it is too soon to tell, but here’s what the story represents to me: the incredible pace of technological advancement in the CRISPR era continues unabated.  Prior to 2012 – LESS THAN 8 YEARS AGO – most people excited about CRISPR probably thought of it as an intriguing way to improve yogurt.  In less time than it typically takes to bring a single drug to market, CRISPR has launched a multi-billion dollar industry, with the first CRISPR-mediated therapies approved for human trials (and, less positively, the first CRISPR gene-edited babies already past their first birthday in China).  If CRISPR prime doesn’t deliver, something else will; I’d put an Amazon-sized bet on that.

 

  1. THE UK BIOBANK FUELS A NEW ERA OF POLYGENIC RISK SCORES FOR… EVERYTHING.

Move over, Iceland.  Your collection of genomic and health history information was good but how can a small island nation with a genetically homogenous population compare with the vast genomic richness of… England?

Okay, so 94% of the half million participants in the UK Biobank are white.  But, as papers appear almost daily, it is hard to deny the fundamental impact of the UKB as a research resource.  Funded in 2002, the dataset combines the results of genomic testing with phenotypic measures of more than 2400 traits, and survey data covering everything from sexual history to political preferences.  And with only a handful of restrictions and a $2500 fee for use, UKB data is available to almost everyone, and it has been used to link common genetic variants with everything from depression to obesity to income.

In turn, this mass outpouring of genetic association studies has spawned a sub-genre of “genetics is not deterministic” PSA’s, like this one from Kevin Mitchell, and I’d like to collectively thank you all for your efforts.

Because volume is the message, it is hard to single out a single UKB-themed story, but in the spirit of reductive end-of-year list-making, let me focus on an article on the genetic basis of same sex sexual behavior published in Science in August.  The authors of this study, which reported on a GWAS of data drawn from the UKB and the 23andMe consumer customer database, identified results indicating genetic associations that accounted for 8-25% of the variation between individuals who had participated in same-sex sexual behavior and those who had not.  The authors were extremely careful to explain that a single same-sex experience was not the same thing as homosexual orientation, and in fact further analyses indicated that there were genetic differences between the two.  Additionally, the article made clear that while patterns emerged in a population, individual results were insufficient to indicate likelihood of homosexual behavior on an individual level.  The authors even constructed a website putting this into more user-friendly language, in case anyone found the Science article inaccessible.

So it could come as a surprise to no one that, 6 weeks later, an app called “How Gay Are You?” went up for sale through the DTC gene-testing marketplace Gene Plaza.  Under intense public pressure from the authors of the study among others, this app was removed in November.  Was it only a bit of harmless fun, like the app that claims to identify your inner superhero?  Maybe not says science journalist Emily Mullin, who pointed out on twitter that the person responsible for the app is based in Uganda, where homosexual behavior can get you the death penalty.  Ha ha adorable.

Sure, this example fails to illustrate the medical value and legitimacy of many UKB-based gene tests reported in 2019.  But it says something profound about how quickly the marketplace moves to commercialize genomic associations, and the difficulty of controlling how the information is used – but also (a bit more optimistically) that a response and clear communication from scientists can mitigate misuse.

 

  1. POPULATION SCREENING

The steep fall of the cost of DNA sequencing has transformed genetic research and made exome sequencing a staple of medical management.  It has also opened up the possibility of population-level screening programs, including research programs like the UK Biobank and the U.S. All of Us project and clinical programs like Geisinger Health System’s MyCode.  Is genetic screening of healthy individuals a good idea?  That depends on the circumstances. How about by government decree, without consent, for purposes of tracking a vulnerable and restive minority population?  Hmmm… pretty sure even George Church and David Ledbetter are a hard no on that one.

But a report by the NY Times in February documented that involuntary “free health checks” of a Muslin minority population by Chinese authorities included facial scanning, fingerprinting and a DNA test.  This perversion of health care is even more nefarious in the context of Chinese repression of the Uighars, over a million of whom are rumored to be in ‘re-education camps’ serving indefinite sentences for the crime of belonging to the wrong ethnic group.  Thermo Fisher, the Massachusetts-based company that provided the equipment used for population sequencing, announced that it has ceased sales to China as information on the genetic testing program began to surface in the news.

How do they plan to use DNA sequence data?  Will individuals be tracked using DNA profiles or groups of individuals sorted by genotype?  I doubt even the Chinese know.  But genetics has always had a dark side, and even the most ambitious of early eugenicists could hardly have imagined the power of population-level sequencing programs, and the toxic potential of new-fangled technology and ancient prejudice.

 

  1. ZOLGENSMA AND THE COMPLICATED MORAL MATH OF MIRACLES

There is no bigger story in genetics in 2019 than the success stories in gene therapy, which have brought help to a handful, and hope to many.  Two years removed from the first FDA approvals in 2017 (two immunotherapy drugs and Luxturna, for a rare inherited retinal disease), the 2019 update includes a handful of new market entries and a robust pipeline, with some tantalizing year-end hints about promising results in gene therapy trials for sickle cell disease and beta thalassemia.  Nowhere is the optimism felt more keenly than the SMA community, where parents now have competing options to treat what was until recently a death sentence for their affected children.

But as this story by the Washington Post indicates, access to those options poses a world of new challenges.  Zolgensma, a gene therapy for SMA, made headlines as the world’s most expensive drug at 2.1 million dollars per patient, and that fact means that insurance companies are going to take a long hard look at who qualifies for the treatment.  This article concerns a toddler turned down for the drug because as a type-III SMA patient she is not severely affected enough to qualify – although she has difficulty walking and can anticipate lifelong disabilities.  Since the use of the medication is only approved for children under two, there’s no room for a wait-and-see attitude.

The economics of gene therapy are built on a model of one-and-done treatment that replaces lifelong care, a promise that in these early days is aspirational at best.  But even if it goes according to plan, the model doesn’t account for children like the adorable, moon-faced Daryn Sullivan, whose lifetime medical costs might not be so outrageous as to make 2.1 million up front sound like a bargain.  With other diseases, off label use might include genotypes that are not the best case scenario for use, where we anticipate improvement not cure.  If it’s the best medicine can do, can we pay 2.1 million for anything short of a miracle?

For all these substantial challenges, the biggest translational obstacle may be something more subtle, captured not in the article but in the comments.  Daryn’s parents, it turned out, knew during pregnancy that the child would be born with SMA and chose not to end the pregnancy.  Will our increasing ability to identify and prevent genetic disease make us less willing to fight the hard fight for access to treatment?  “I had the deepest sympathy for the Sullivans,” one reader wrote, “until I read the part where they KNEW their baby was doomed to a terrible wasting disease, but continued the pregnancy anyway.”  A quick review showed about 10% of the 320 comments said something similar: “people create children with disorders and then demand that everybody else pay for their treatment no matter what the cost.  Shameful.”

In the past 10 years, we have addressed many of the technical challenges to gene therapy.  In the next decade, we will have to confront the potentially even more challenging issues of access and empathy.

 

THAT’S IT FOR ME IN 2019!  HAPPY NEW YEAR, EVERYBODY!!!!  GOOD LUCK TO US ALL IN 2020 (WE’LL NEED IT).

 

 

 

 

 

 

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by | December 29, 2017 · 10:17 PM

Top Ten Stories in Genetics in 2017

Mark it in your calendar: 2017 was the year when gene therapy (broadly defined) became something more than hypothetical.  Hard to talk about 2017 as a great year, but that’s the storyline in genetics.  Here’s the countdown:

  1. Ohio Bans Abortions for a Fetus Affected with Down Syndrome

In December 2017, Ohio became the 3rd state to criminalize abortion to avoid the birth of a child with a genetic condition. The first law was passed in North Dakota in 2013 and remains on the books, and a similar measure in Indiana that focuses specifically on Down syndrome was enjoined by court order after an ACLU challenge.

Ohio’s law makes it a felony to perform an abortion if the patient’s motivation is to avoid the birth of a child with Down syndrome. These laws appear unlikely to be enforced: unconstitutional under Roe v Wade, they should not survive a court challenge, and if they did, they would be incredibly difficult to enforce. Still, there are several reasons why it is worth paying attention to what must now officially be called a trend.

First, these laws didn’t pop up organically, and they indicate that therapeutic abortion is on the radar of anti-abortion groups. Expect more of the same, and battles on related fronts, including insurance coverage for prenatal testing.

Second, even if the law is never enforced, it could affect practice. A woman’s motivation is hard to prove, but the motivation of a genetic counselor or a physician discussing termination after a diagnosis of Down syndrome is crystal clear, and could put them at risk. Even a distant and unlikely threat of a felony prosecution is a great disincentive to any clinician. Discouraging counseling may pr may not prevent abortion but it absolutely deprives couples of the good, unbiased information that Down syndrome advocates have been working on for years. And as usual, it increases disparities in care for individuals with fewer resources or less education.

Third, polling suggests that a slim majority of the country believes abortion should be available for pregnant women when the fetus faces cognitive impairment, but it’s emotionally tricky territory and norms may shift to make therapeutic abortion more stigmatized. There’s a reason why the second and third iterations of the law specified Down syndrome: this is a public relations campaign and Down syndrome kids present a sweet and photogenic face. “Every Ohioan deserves a right to life, no matter how many chromosomes they have,” said the head of the Ohio Right to Life, neatly eliminating the difference between a fetus and a child.

Fourth, expect a whole lot more of this if we lose Roe v Wade.

  1. STAT names the Swiss Army Knife the top CRISPR metaphorScreen Shot 2017-12-29 at 7.26.31 PM.png

Bacteria have been using CRISPR for aeons, but humans have only had it in their gene editing toolkit for five years. In that short span, technical advancements have occurred so quickly that 2012 CRISPR is starting to feel a bit old school. Some of these innovations improve the original CRISPR search-and-delete functionality – reducing off target effects, for example, or improving the odds of replacing deleted DNA segments with a scripted sequence delivered via a template. Other advancements add new types of functionality. In 2017, researchers introduced a modified CRISPR system uses the same search function but doesn’t cut; instead, it alters gene expression by changing the elaborate system of packaging that turns gene on or off. In another iteration of CRISPR search-and-don’t-cut functionality, scientists from Harvard and the Broad Institute have pioneered a technique called base editing, which locates a specific spot in the DNA sequence and replaces a single base through a series of chemical reactions without the riskier business of inducing a double-stranded break. In October, researchers from China announced that they had tested base editing in human embryos, and were able to correct a mutation that causes the blood disease beta thalassemia 23% of the time.

The proliferation of CRISPR varietals led writers at STAT to give top honors to “the Swiss army knife” in a ranking of CRISPR metaphors (runner up: “organic photoshop”).

 

  1. Harvard’s George Church opens up the George Church Institute in ChinaScreen Shot 2017-12-10 at 4.37.03 PM.png

Synthetic DNA made significant steps forward this year, starting with an announcement in January that researchers at the Scripps Institute in La Jolla have produced a modified a strain of E coli whose DNA has six rather than the usual four base pairs. The following October, in a story that my be the epitome of 2017, Harvard professor George Church traveled to China to announce the opening of the eponymous George Church Institute of Regenesis. This collaboration with Chinese giant BGI has plans to develop clinical applications of synthetic biology. The investment of substantial resources in artificial life forms and bio-manufacturing is one indication of where we are headed; sadly, the decision by one of America’s great science talents to launch an ambitious project halfway across the world may also prove to be a sign of things to come.

 

  1. Popular Culture Discovers CRISPR

This was the year I read my first sci-fi novel about a world where children (and pets) are routinely gene-edited. Although it was a dystopian vision, I have to admit I was intrigued by the tiger-ized house cat…

CRISPR has definitely captured the imagination of a good part of the universe, and my sense is that the jury is out on whether our new powers of gene editing are going to be viewed as cool or creepy. Meanwhile, here’s some unexpected places where CRISPR popped up in 2017.

On Jeopardy!

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In Ashton Kutcher’s twitter feed:

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Graffitied on the mean streets of San Francisco:

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This is a sleeper pick at number 7, but I believe it’s important to understand that people are paying attention, because (like the rest of us) they don’t yet know what to think. The early uses of CRISPR will have a great impact on public opinion, and very likely on support for research, development and commercialization of gene editing down the road. It’s something to think about.

 

  1. The FDA Changes Direction on DTC Genetic Testing

The FDA executed a remarkable about-face on direct-to-consumer genetic testing in 2017, beginning in April when the agency approved a new iteration of their SNP scan for liability to disease, 3 ½ years after they shut down sales of the alpha version, claiming it posed a risk to the health of those who bought it. In addition to signing off on testing for 10 complex conditions where the genetic contribution is important but not definitive, the FDA announcement established some ground rules that could be applied to other tests and other companies. First, the decision identified 23andMe as what they called a ‘trusted provider’ and indicated that having been so designated, they would not have to jump through regulatory hoops for every new test, and would be exempt from premarket review. Second, the agency created a category called “genetic health risk (GHR)” tests, as distinct from genetic tests that were diagnostic, which were explicitly excluded from exemption.

Presumably, the agency’s goal was twofold: to remove impediments to the growth of DTC, while carving out some rules for what belonged in that realm, as distinct from what belonged in a clinical setting. In November, the FDA made this explicit, announcing its intention to establish a new regulatory structure for GHR tests which would formalize the ‘trusted provider’ approach through a one-day FDA review, allowing them to introduce non-diagnostic tests and carrier screens without further premarket scrutiny.

This change in governance is likely a response to what is happening in Washington, where anti-regulatory sentiment is rife, and may also be due to changes in the marketplace, with major players like Illumina and Google making sizeable bets on DTC genetic testing ventures. There is little question that the FDA moves have had a big impact, and the fledgling DTC industry appears to have spread its wings and taken off. Strong Christmas sales for both Ancestry.com and 23andMe indicate that consumers are willing to give genetic testing a try; sustained success may be contingent on how that experience goes for the recipients.

 

  1. First RNAi Drugs Show Promise in Human Trials

Many of the early targets of gene therapy are diseases caused by a single missing or defective protein, and the goal in these cases is to introduce a gene that will produce what the body is lacking. Despite the fact that we have not been very successful to date, it is a simple model; often replacing a small fraction of normal production is enough to treat or effectively cure the disease. In some diseases, however, the problem is not the absence of a normal protein but the presence of an abnormal one which disrupts function or damages healthy tissue. In these cases, you can’t simply (‘simply’) replace what you don’t have but must find a way to silence the gene product that is causing all the trouble.

One way to do this is to intercept the RNA messages before they are made into protein via RNA interference – designer RNA’s that find and bind to specific transcripts to prevent translation. Like many other forms of what might broadly be called gene therapy (I’m not into fights about semantics so don’t @ me), RNAi has not fulfilled it’s conceptual promise to date, but that seems to be on the verge of changing. In October Ionis Pharmaceuticals launched the first human trials of a RNAi drug for Huntington’s disease, and in November a Cambridge-based company called Alnylam announced that its RNAi drug for hereditary ATTR amyloidosis was showing success in phase 3 trials and might be up for FDA review in 2018.

 

  1. In Vivo Gene Editing Mitigates Deafness (in Mice)

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In another late entry into the Top Stories of 2017, researchers from the lab of David Liu published a December article in nature describing the use of in vivo gene editing to facilitate hearing in mice bred to exhibit a form of genetic deafness found in humans. Mice injected with CRISPR-Cas9 complexes showed more hair cells and improved response to auditory testing. While it is always good practice to remind ourselves that not everything that works in rodents works in people but… in vivo gene editing is a remarkable technical achievement with incredible potential. Brought to you, by the way, by a co-founder of Editas Medicine, so this maybe this blog post can double as a stock tip. 2017, ladies and gentlemen.

 

  1. A Gene Therapy Ready for Prime Time at Last!

We’ve been talking about gene therapy for so long it seems like old hat, except that this particular old hat has never been thrown into the ring… until now. On December 19th, the FDA approved Luxturna, a gene therapy for blindness. First of its kind, Luxturna introduces a gene into retinal cells by a viral vector and, in cells where uptake of the wildtype variant increases the production of normal protein.

Eyeballs are a uniquely accessible body part, making them low-hanging fruit for gene therapy, but low-hanging fruit is the place to start, and the take-home point here is that the new and improved gene editing technology and gene delivery systems are for real, as is (finally) gene therapy. Coming soon: gene therapies for blood-based diseases such as hemophilia and sickle cell. Still to be determined: how much all of this will cost.

 

  1. Immunotherapy Delivers a One-two Punch

The cancer field has been buzzing about Car-T therapy for years, hopeful that this new class of therapies designed to harness the body’s own immune system would not only expand the range of cancers we could fight, but do so in a targeted fashion that would reduce the toxicity associated with current chemotherapies. Immunotherapy has been through several rounds of hype-and-hate before getting out of the clinical trial phase, as stories about patients rescued from the deathbed have sent up smiley face trial balloons and deaths from unanticipated side effects have popped them.

After all the anticipation, approval of the first two Car-T drugs came only weeks apart, with Kymriah, a drug for pediatric leukemia, approved in August and Yescarta, for some forms of B-call lymphoma, following close behind. All the usual caveats apply – real-world safety and efficacy still to be worked out over time, and price price price price price plus access, but without setting that aside, I want to take a moment to congratulate everyone who worked to create and validate this new and important class of cancer therapies.

 

  1. The Boy who Got New Skin Is Everything You Ever Hoped For in a Stem Cell Success Story

Screen Shot 2017-12-29 at 7.38.53 PM.png

I was six paragraphs into Ed Yong’s story about a boy with epidermolysis bullosa when I realized it was going to be my top story in genetics for 2017. How many things are there to love about this story? First of all, it’s about a cure for EB, a disease that disrupts the normal structure of the skin, making it fragile, so that it is prone to rupture and blister. In bad cases, people are plagued with open sores that will not heal. It’s a biblical plague of a disease, and this kid was in terrible shape – shape – seven years old, and headed to hospice care.

And they fixed him.  This is also a stem cell success story, joining the list of finally-finally-at last therapeutic success stories in 2017. Doctors removed a small patch of precious intact skin from seven-year-old Hassan and sent it to researchers in Italy, who isolated and corrected skin stem cells, and then used them to grown sheets of skin in which to sheath the dying child. They replaced an astounding 80% of his old skin and – here’s the part from paragraph six – less than a year later he is back in school, playing sports and living the life of a normal child.

I promised myself never to talk about these high tech miracles without discussing cost and access, so here I raise relevant questions: what’s this going to cost, and who will be able to get it?   Honestly, I have no idea.   And for the record, this technique won’t work for all variants of the disease.  But there is a lot to celebrate.

It seems strange to talk about 2017 as a series of victories for humanity, but the year in genetics was full of hope and promise, and nowhere was that contrast more on display than here, in the a story of a global community coming together to save a life. A Syrian child, treated by German doctors together with Italian researchers who were mentored by an American pioneer…  It was the epitome of 2017 in genetics, though sadly not the epitome of 2017 in any other sphere.

 

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by | September 20, 2017 · 5:50 PM

Supporting Our Patients and Their Right to Choose Means Opposing Graham-Cassidy

If you are a genetic counselor supporting the Graham-Cassidy proposal to replace Obamacare, you are a rare bird. Most genetic counselors – most medical professionals – most Americans for that matter – are opposed to this bill, because it compromises our ability to provide basic, essential medical care for people in need. It is not in dispute that millions of American will lose health insurance under this bill. Those with health insurance will generally pay more for less. Many of the changes remove existing protections on which our patients are particularly reliant. Here are some examples:

 

PRE-EXISTING CONDITIONS

The bill will allow states to eliminate regulations on pre-existing conditions, so that people will risk losing coverage if they change or lose their jobs. This is a disaster for individuals with chronic health problems including genetic conditions, and potentially a disaster for individuals who carry susceptibility genes. Although you might make the case that GINA should protect those individuals in theory, in practice it becomes hard to draw the line for what constitutes an existing disease in an at-risk individual. For instance, if a Lynch Syndrome carrier requires special screening and has polyps removed, are they preventing disease or symptomatic? Will a subsequent carrier argue that they already showed signs of Lynch and therefore are not covered for further screening or colon cancer? The fact is that Obamacare arrived before these questions got answered, and there is a very real risk that GINA protections will be eroded when the actual lines between pre-existing and manifest disease are drawn.

 

PRENATAL CARE

The new law allows policies to limit or even eliminate coverage for prenatal care. This logic of this abomination – the disgusting and perverse logic to be voted on by a collection of doddering old men who apparently were not of women born – is that pregnancy is not a disease but a choice, and affects only subset of women, so that others should not be asked to bear the costs. This decision abrogates the most fundamental obligation of civil society, which is to raise the next generation. You have one job, civilization. One job.

 

Every politician who argues that it is not fair to ask everyone to pay for insurance that covers prenatal care should be asked if they believe it is fair to ask women to pay for policies that cover prostate cancer care. Or who it is they believe will care for them in the nursing home, or fight for them in their wars, or protect their streets or teach their grandchildren or write their history books if not the next generation of Americans.

 

But you see here I am getting worked up, and the very righteousness of this anger masks another aspect of this change that has particular resonance for genetic counselors: limiting access to prenatal care limits access to prenatal testing, and limiting access to prenatal testing to those with more money will mean that those genetic diseases and conditions for which we can test will change the essential nature of genetic disease – no longer something that happens to everyone, it will become an affliction of vulnerable individuals. I wrote about this in a recent essay, calling it the Ghettoization of Genetic Disease, and this bill will help make that dystopian prediction a reality in the near term.

 

LIFETIME CAPS AND DISABILITY CARE

The Graham-Cassidy bill eliminates protections on lifetime caps, meaning that many individuals with chronic conditions, including genetic diseases, may end up without coverage. In addition, the cuts to Medicaid and other federally funded programs would radically reduce support for individuals with disabilities.

 

On the surface, flat out, this is heinous and cruel. Beyond that, for the genetics community, this undercuts the promise we make, by implication, to every woman or couple who decides to move forward with a pregnancy affected by or at risk for genetic disease. Supporting choice in reproductive decision-making is not a simple matter of holding someone’s hand through a difficult day. Supporting autonomous decision-making as a field means fighting for those individuals and families to be supported throughout the lifecycle.  The choice to live in a world that offers no support or resources is no choice at all for most people.

 

LET’S TAKE A STAND

It is extremely unfortunate that healthcare, a subject of mutual concern and importance to all Americans, is now held hostage to the ignorant, pettiness of slogans on signs that angry partisans wave at campaign rallies. No professional organization wants to get embroiled in party politics. On the other hand, there are times when everything you believe in is threatened and you have to take a stand. I believe this is one of those times.

 

I’m hardly alone in this. The AMA released a statement yesterday opposing Graham-Cassidy. So have many other groups representing healthcare professionals and patients, a number of them listed here in Jimmy Kimmel’s eloquent denunciation of the bill (comedians must lead when politicians are clowns, I suppose, and what else can he do when our government is beyond satire?).

 

So please, NSGC, make us proud with a statement against this terrible bill. Let’s take a stand for our values and, more importantly, for our patients.

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by | August 5, 2017 · 9:42 AM

Human Germline Editing: our crazy, scary, wonderful future is coming, but not quite yet

Publication this week of a paper by reproductive biologist Shoukrat Mitalipov and others put the subject of editing little baby humans front and center – above the fold news in the NY Times. Universally, the Mitalipov study was recognized as a milestone, and so it appears to be – a milestone on our journey to…wherever it is we are headed.

 

What did they do, and why is it important? Mitalipov improved greatly on previous efforts at germline editing, targeting embryos created using donor eggs and sperm carrying a pathogenic variant in the MYBPC3 gene associated with hypertrophic cardiomyopathy. Modification was successful over 70% percentage of the time, no off-target effects were detected, and only one of the 58 embryos was found to be a mosaic of altered and unaltered cells. While significant safety and efficacy concerns remain to be addressed, this work goes a long way toward validating the idea that, sooner rather than later, clinical use of this technology will be a realistic possibility.

 

The experiment raised hopes, but also some questions. CRISPR is often described as a DNA version of a search-and-replace function in a word processing program, but CRISPR itself only does search-and-remove. The ‘replace’ part leverages the cell’s own machinery for fixing breaks in DNA, and its innate penchant for tidying up any loose ends. Quick to the breach, cells can often be coaxed into using a template for the repair if one is provided along with enzymatic scissors and a guide RNA, allowing us to insert a custom DNA sequence. This bespoke DNA can be anything, but in this case it was meant to be a benign version of the MYBPC3 gene. In a surprising development, the cells preferentially ignored the synthetic template and used the unaffected version on the sister chromosome as a guide instead.

 

This had the desired effect of introducing a functioning wildtype gene, but if it is not overcome as a technical issue, will limit the range of what can be achieved via gene editing. This model doesn’t work at all with recessive disease, where there are two copies of the pathogenic variant. Additionally, it would not allow for the introduction of DNA sequences other than what is carried by a parental allele – a capability which is, I would argue, the truly unique feature of gene editing.

 

Articles about CRISPR may (and usually do) talk about its potential to prevent Mendelian diseases like Huntington’s or sickle cell, but we are already capable of preventing transmission of these diseases using IVF with PGD to identify embryos that are unaffected. Yes, as has been pointed out, this is not foolproof. A round of IVF may produce no unaffected embryos. In rare circumstances, one parent may be homozygous for an autosomal dominant disease. These are non-trivial events when they occur but they are rare and limited circumstances. For the rest, replacing one expensive and complicated technology with another is incremental progress at best, and not the reason why this story was A-1 on the NY Times website. Media interest, let no one be confused, was about the potential of CRISPR to produce what they referred to (inevitably) as designer babies.

 

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Antonio Regalado of the MIT Tech Review decodes media coverage of human genome editing

 

Can the technology produce designer babies? This would be an easier question to answer if designer babies were actually a thing that you could define, but they’re not. Generally, what people mean by ‘designer baby’ is one created through any use of reproductive technology to ensure specific traits, as opposed to using identical technology to avoid diseases. The problem with this is that drawing the distinction is a bit of Impressionistic painting – clear from a distance, but blurring together when you get close. A number of articles this week suggested that designer babies can’t happen because traits are not something that can be manipulated by tweaking a gene or two (here and here). This is comforting but may not hold up. It’s fair to say that you can’t tweak general intelligence – but what about, for example, executive function? And while we’re on it, would that be increasing intelligence (bad) or avoiding ADHD and other mental health problems (good)?

 

But this is leading me into rabbit holes, where we debate what is or might be or could be possible, when just now I want only to say that the potential of gene editing to add an entirely new dimension to what we can currently offer is bound tightly to its ability to introduce DNA sequences that are different from what either parent can contribute. When we are able do that, we can expand the concept of what it means to ‘choose’ a child’s genotype. We can add rare variants that confer some protection or competitive edge. We can even contemplate adding synthetic variants designed in a lab and not borrowed from natural experiments. When move past embryo selection to embryo improvement, we will have our little Gucci baby whose possible existence causes so much consternation.

 

So does this week’s blockbuster paper put us closer to that day? Yes, because the technology has moved forward a giant step. Not that technology ever moves backwards, but the speed with which it has improved is staggering, and while momentum is not going to carry it over the remaining hurdles like a hot wheels car going loop the loop, it does make it easier to assume that all technological barriers will eventually fall. But at the same time, the template surprise reminds us that every step forward reveals another twist in the road.

 

Are we almost there?  Who knows. If 2016 taught me anything, it was to stay out of the prediction game.

 

So what would a wise republic do? Coincidentally, a workgroup under the auspices of the American Society of Human Genetics published a paper yesterday in the AJHG laying out recommendations for public policy on human germline editing. The position statement was approved by ASHG, NSGC and 9 other organizations from six continents (full disclosure: I am one of the co-authors). The take home point is that modification of the human genome (egg, sperm or embryo) would be premature at this time but may be justified in the future, providing that there is a compelling medical rationale, an evidence base to support its use, ethical justification and a transparent public process to solicit and incorporate stakeholder input. In the interim, the organizations encourage governments to permit and to fund work like Mitalipov’s that investigates the potential of human germline engineering.

 

Having been a part of this group, I can attest that we thought long and hard about this aspect of the statement, and that we made it despite our concerns that this technology holds risks for both individuals and society, including the potential to increase existing inequities in health and quality of life. We may try and regulate use and norms such that we get the upside and not the downside, but we must acknowledge that to a large extent the two are inextricable.

 

Speaking only for myself, I can say that I see the allure of a form of intervention that might prevent rather than merely treat sickness and suffering, even as I sympathize with those who worry about the impact of the technology on future generations. If the choice were mine, it would be a difficult choice. But in the end, what I recognize is that we are not given a choice between going backwards and going forwards. The truth is that gene engineering is going to happen.  No one government or individual is going to stop it — the world is too big and the stakes are too large. The questions that sit in front of us are not yes or no, but where, how and under what circumstances. I believe that a thoughtful society should engage with the technology, providing capital and oversight, resources and regulation. To turn our back is to sacrifice whatever leverage we could bring to bear as we establish norms for use, and to cede our leadership role in the scientific community at the dawn of an era, the start of a journey to…wherever.

 

 

 

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by | April 9, 2017 · 7:32 PM

FDA and 23andMe change their Facebook status to ‘in a relationship’

In 2007, 23andMe launched their personal genome scan, a SNP-based test that offered consumers an estimate (some might say a guess) as to how certain elements of their genotype might contribute to their likelihood of having an array of traits and diseases. It was a great success, if success was to be measured in ink and column inches rather than actual dollars. Anne Wojcicki’s company quickly came to represent the embodiment of direct-to-consumer genetic testing, an icon of what was more a movement than an industry.

 

For that reason, six years later, when the FDA surprised 23andMe with a cease and desist order for their genome scan, it could reasonably be taken as a rejection of not only one company but the entire DTC ethos. At the time, many canny observers pointed out that the FDA’s drastic move seemed to have more to do with 23andMe’s attitude than it did with any specific risk posed by testing. As Duke University genetic professor and trenchant observer Misha Angrist was quoted as saying at the time, the FDA missive read “like the letter of a jilted lover…‘We went on fourteen dates! We exchanged all these e-mails! We held hands in the park! Now you’re telling me, “Fuck you,” and kicking me to the curb.’ ”

 

In response, a chastened 23andMe kept a toe in the DTC puddle by offering testing for ancestry and non-medical traits like sleep patterns and eye color while negotiating a slow courtship of the regulatory body. Eventually they got flowers back from the FDA – or rather a single flower, permission to offer just one carrier test, for the aptly named Bloom syndrome. But this blossom, like many others, was freighted with greater significance, and now that they were friends again the FDA decided that other DTC carrier tests would no longer require individual premarket approval, allowing 23andMe to add back a layer of medical testing to their business model.

 

The FDA drew a line between giving out information on carrier status (okay) and giving out information that was diagnostic (not okay). This created the odd situation where 23andMe could tell a customer if he or she had, for example, one CF-causing variant but was forbidden to inform them if they had two, since that was a presumptive diagnosis. Let’s leave aside how confusing this all gets, since sometimes people can have two disease-causing variants and remain healthy, and sometimes carriers can have medical complications. I’m not even going to mention that. See how I didn’t mention that? The bottom line was that 23andMe could inform you of a risk for something that might happen, but only if it was a mere possibility and not if it was certain or highly likely.

 

Two years later, the FDA has come out with another announcement – this time I assume that 23andMe is less surprised than the rest of us – that will expand the universe of what is available through DTC testing. The company will now be allowed to provide testing for susceptibility to 10 diseases and conditions with significant health implications, including late-onset Alzheimers disease, Parkinson’s. celiac, Gaucher’s disease type 1, hemochromatosis, and others. Again, this isn’t just a bouquet of flowers being handed out to a patient suitor. It signifies a change in thinking at the FDA about the value of DTC genetic testing, which they noted in their press release “may help to make decisions about lifestyle choices or to inform discussions with a health care professional.”

 

No but really this is getting embarrassing get a room you two.

 

The FDA announcement indicated that these 10 diseases were merely a beginning. In the future, 23andMe and other trusted practitioners will be able to introduce tests with less regulatory scrutiny. The FDA’s commitment to a streamlined and less burdensome process demonstrates a new interest in making DTC genetic testing widely available.

 

The important thing, emphasized Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, was that consumers did not come away believing that genetics was destiny. “…it is important that people understand that genetic risk is just one piece of the bigger puzzle, it does not mean they will or won’t ultimately develop a disease.” For this reason, the FDA has doubled down on it’s practice of differentiating between susceptibility and diagnosis.

 

Conceptually, this makes sense. Practically, in some cases, it creates a situation where DTC customers can access the sort of probabilistic information that we are generally loathe to give out in a clinical setting – like their chance of getting late-onset Alzheimer’s disease – but are blocked from getting exactly the sort of definitive, actionable information we value the most.

 

Possibly, this might serve to differentiate the realm of DTC testing from the kingdom of clinical medicine. Genetic counselors, often DTC skeptics, might feel more comfortable adopting a live and let live approach if areas central to GC practice like susceptibility for cancer and heart disease were reserved for the clinic. Still, when it comes to ApoE, it is a bit of a paradox that the solution to information deemed too hot to handle by counselors is to give it out with no counseling at all. The impact, I am inclined to believe, will be to speed the integration of probabilistic testing into genetic practice. In the meantime, it will almost certainly herald a period of rapid expansion of health and wellness testing in the DTC space.

 

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by | March 15, 2017 · 4:23 PM

Will H.R. 1313 Allow Wellness Programs to Undermine Your Rights Under GINA? Inquiring Constituents Want to Know…

It’s 2017, and it’s hard to keep track of the reasons to be outraged, but here’s one with special relevance to the genetics community: H.R. 1313, the Preserving Employee Wellness Programs Act (alternatively entitled H.R. 666, the Unfortunate Erosion of GINA Act).

There are two main questions we should be asking about H.R. 1313. One, what does it do? And two, why does it exist? For the first, what the law would do (if passed) is allow so-called wellness programs to circumvent the limitations on data collection by employers set out in the genetic non-discrimination act (GINA) and the Americans with disabilities act (ADA). I say so-called wellness programs because in point of fact they have not generally been demonstrated to make people, shall we say, well-er. Which raises the question of why Congress is so keen to make sure they are maintained, but we will get into that later.

Under GINA, employers are not allowed to purchase, request or require genetic information from their employees. The assumption behind this point of law is that employers who had that information might be tempted to try and reduce their exposure to risk by discriminating against those in their risk pool (or their dependents) with increased susceptibility. Alternatively, they might try and use genetic information as a part of decision-making about promotions or assignments. Some of the people attacking the bill have pointed out that attempts to use predictive genetic information are at present likely to be absurdly ineffective and misguided, but this only makes the acts of discrimination more random, not more (or less) nefarious. If they could do it with pinpoint accuracy, it would still be unfair.

Exceptions for wellness programs already exist under GINA, to allow these programs to ask the participant about genetic conditions or genetic testing. As the law stands, the employee must participate voluntarily, and individual identifying information must be collected by a licensed or certified health professional (including, specifically, a genetic counselor) and cannot be shared with the employer except in the aggregate. As for voluntariness, H.R. 1313 would alter this dynamic by sleight of hand – employers are not allowed to charge people more for insurance if they don’t participate, but they are allowed to offer incentives for employees who do participate, and those incentives can be up to 30-50% of their total healthcare contributions. Got that? We’re not charging you more, people who don’t give us your genetic information, we are simply charging the other people less.

 (Sidebar: perhaps we can get corporations to introduce wellness programs that require employees who participate to vaccinate their kids, while the ones who do not pay thousands of dollars more per year in health insurance costs. Vaccines, after all, are the best validated wellness program that we have. Just a thought.)

 The second and most serious charge that has been made about H.R. 1313 is that it would eliminate privacy protections that exist under GINA, and give your employer access to genetic information about employees and their family members. This has been reported in a number of places (in the NY Times here and in STAT here) but is disputed by the NSGC fact sheet circulated on, forebodingly, the ides of March. The bill doesn’t refer to the issue of sharing genetic information specifically, and it seems reasonable to assume that those protections you have under GINA would be in force unless specifically taken away, HOWEVER, there’s obviously room for doubt, given all the doubt. Take home point: the bill should be amended to include a clear message that genetic information is private and cannot be shared with employers (or, for that matter, sold – as commonly happens with wellness programs today).

Which brings me to my second question: why does this bill exist? Identifying the beneficiaries might shed some light on what it is intended to do. Employers might like the bill, if they see it as allowing them to shift health care costs to non-participants via the incentive system (lower costs for some being alternately described as higher costs for others). If we are being pie-eyed optimists, we could imagine that employers are just determined to see you healthy, although in that case they might be put off by the absence of any compelling evidence that these programs work. If we are being conspiracy theorists, we might wonder if some employers see an opportunity to obtain information on the health and health risks of employees and their dependents to which they are denied access under GINA.

Obviously the law is a boon to the ‘wellness’ industry, which Congress is nurturing with this sack of high quality manure while asking in return only that the wellness program not be “highly suspect” as a method to “promote health or prevent disease.” Ah, the old, ‘not highly suspect’ standard.

Perhaps, say you, another beneficiary of the law is the employee who receives a rebate for being healthier. Yes. I’m all for lower health care costs. But since the wellness programs don’t actually make employees healthier, but may identify employees (and their dependents) with more health risks, their benefits come by chasing people who need insurance out of their insurance pool. Companies could keep their own overall costs the same by dropping everyone’s premiums by some intermediate amount, which would help all employees with the added benefit of not being a human rights violation. Food for thought.

On March 8th, the American Society of Human Genetics (ASHG) came out with a strong statement opposing H.R. 1313, quoting director of science policy Derek Scholes as saying that “If enacted, this bill would force Americans to choose between access to affordable healthcare and keeping their personal genetic and health information private….Employers would be able to coerce employees into providing their genetic and health information and that of their families, even their children.”

The response from NSGC has been more nuanced, prefacing a statement on their concerns about H.R. 1313 with the caveat that “NSGC supports the collection of family health history information.” Without taking an official position on the bill, NSGC has indicated concern about voluntariness and privacy protections, proposing that in its final version, “the bill should explicitly reaffirm the GINA discrimination protections, roll back penalty language altogether, and limit rewards, among others. NSGC would also support further study of the value of wellness programs, and their focus to ensure the programs can indeed positively impact health.

Privately and publicly, I have heard comments from members of the genetic counseling community who are concerned about H.R. 1313. This bill has gathered a fair amount of negative attention and there is a good chance it does not move forward, at least not in its current form. I don’t say this to discourage grass roots activism; in fact it’s the opposite – evidence suggests that public pressure is having an impact. So call your Member of Congress! (we all have our elected representatives on speed dial by now, right?). Here’s a quick summary of three points worth making:

  1. Participation in any program that includes gathering genetic or family health history information on the participant and/or family members should be truly voluntary, and should not be associated with substantial rebates or incentives.
  1. Wellness programs should be explicitly required to conform with the privacy protections for genetic and family health history information that have been established by GINA and the ADA. Congress should pass no laws that erode or diminish these important civil rights protections.
  1. Laws creating special exemptions or accommodations for wellness programs should include a standard for wellness programs based on an objectively assessed, documented record of improved health outcomes.

 

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