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ERIC GREEN: Okay. Well thank you all for your indulgence, allowing us to do that announcement,
unusual but highly appropriate way to start Council. So we will now proceed to my Director's
Report. And I guess I'm the thing standing between you and lunch. But, nonetheless, the
only thing else we have to do this morning.
I want to remind you that the open session of this meeting of the National Advisory Council
for Human Genome Research is being webcast live. And, as we now do routinely, the resulting
video archive and various associated documents will be made available as a permanent archive
that can be accessed through NHGRI's website, genome.gov.
Let me start off my Director's Report by personally thanking the outstanding members of our Advisory
Council. Besides being a great looking group, as documented in this photograph that we took
back in February, you continue to be immensely helpful to me and to my staff, both during
the actual Council meetings, but also, in various ways that we call on you for your
service, both individually and collectively.
And, as I look at this picture, I will tell you that I'm reminded that I think I've personally
had important conversations with almost every one of you since the last meeting in February.
And meanwhile, I know that many of you have attended key NHGRI workshops and various critical
conference calls, really just in the past few months. So in short, you've been-- have
been and continue to be generous with your time. And your input is incredibly valuable.
And, I can assure you, much appreciated.
The other thing I noticed about this photograph is I don't know if it was an artifact, the
angle that it was taken, but there's some artifact with Jim Evans going on. He looks
like this incredible shrinking-- I think it's you're standing next to Howard or something--
you can barely see you. [laughter] So I thought maybe something weird happened. What did you
do there?
Is that a thing? Okay.
[off microphone]
You are shrinking? I think next time we take your picture-- I don't know-- We won't put
you next to Howard next time. That was not very nice. So okay.
For new Council members, which is mainly Tony, in this case, but also to visitors and web
viewers of our Council meeting, I want to make you aware there is an electronic resource
associated with my Director's Report that's available at the URL at the bottom of the
slide. And this resource is analogous to supplemental materials associated with the published paper.
And so the slides that I am showing during my Director's Report are also available electronically
at this website, both as a PDF file and as a PowerPoint file.
And, for slides that are associated with specific documents or relevant website, there is a
document number on the bottom right, which simply references materials that you can access
through the website shown on this slide. In addition to the video archive that I mentioned
earlier, the entire site, all the linked documents will be archived on NHGRI's website as a permanent
historic archive.
Specifically talking about the open session of this Council meeting, there'll be multiple
other presentations. My report is tailored around these presentations. And by that, I
mean I won't discuss in detail the topics that others will be covering in greater depths.
We have several general topics to discuss in the open session, which these presentations
will begin after lunch.
First we're going to have an update on the NHGRI training portfolio by Bettie Graham.
And then Bettie will also give a presentation on a new NIH policy on applicants with more
than $1.5 million dollars in grant support. And then, there'll be an update on the X chromosome
program announcement by Anastasia Wise. In addition, we will have presentations and discussions
about two concept clearances, one on genomic sequencing in newborn screening disorders
by Anastasia Wise. And then one on a clinically relevant variance resource by Erin Ramos.
And finally, we'll have one program update, that on the 1000 Genomes Project. And that'll
be given by Lisa Brooks.
So, for the rest of my Director's Report, I'm going to talk about these seven areas.
They should look familiar to you, because this is the framework I now use for each of
my Director's Report because it seems to work. And so I'm going to start off by giving you
some general NHGRI updates.
Well, as we discussed at the last Council meeting, I have proposed to reorganize NHGRI
in a fashion that mostly affects the extramural research program and, to a lesser extent,
the Office of the Director. As a reminder, this is a relatively formal process that involves
multiple steps, as actually stipulated by the NIH Reform Act. That process is proceeding,
albeit not at lightning speed. But I can report that the required approvals are now being
sought at the Department of Health and Human Services. And we're hopeful-- it's left the
NIH-- And we're hopeful that the process might reach its end at some point this summer, after
which we would aim to implement the new organizational model as quickly as possible.
Now, as some of you may be aware, Greg Fiero, who was the founding Chief of our Genomic
Healthcare Branch, has been splitting his time, for the last two and a half years, between
working as a practicing family physician, and also in the family medicine residency
program at Maine-Dartmouth, and at NHGRI on topics related to genomic medicine. Unfortunately
for us, beginning in August, Greg will turn his full-time attention to his practice and
residency activities.
His accomplishments and contributions to NHGRI have been many since he first arrived in 2006,
and have included things like leading the charge on family history, both through expansion
of the U.S. Surgeon General's web-based Family History tool, and in NIH, State of the Science
Conference on the topic.
He also led the series of reviews in the New England Journal of Medicine on Genomics in
Medicine. And, under his leadership, the Genomic Healthcare Branch established important tools
for health, professional education, through web-based resources such as Genetics and Genomics
Competency Center-- or G2C2, and G3C, a new resource that is generating interactive genomics
case studies for use in continuing education across health professional communities.
Greg asked me to express his gratitude for the privilege of working with all of you,
and for NHGRI for the last five-plus years. And I would like to personally take the opportunity
to thank Greg for his tireless work and deep commitment to the mission of the Institute
and to the work needed to make genomic medicine a reality. One final note, Greg will soon
become a contributing editor for JAMA in the area of genomics.
Also pleased to report that Teri Manolio, director of NHGRI Office of Population Genomics,
received not one but two prestigious honors since the last Council meeting. First she
received the 2011 Department of Health and Human Services Secretary's Award for Meritorious
Service for her exceptional leadership and coordination of the Department's response
in developing a research plan for studying the health effects of the Gulf of Mexico oil
spill.
And second, she was elected to the Johns Hopkins Society of Scholars. This honor is given to
former Johns Hopkins University students or trainees who have made outstanding contributions
to science and new knowledge. So congratulations, Teri, times two.
So, moving on to NIH updates. First update is a good one. Gary Gibbons has been selected
to be the new Director of the National Heart, Lung and Blood Institute. Dr. Gibbons is the
founder and current Director of the Cardiovascular Research Institute at Morehouse School of
Medicine, where he also serves as Chairman of the Department of Physiology.
We know Gary well at NHGRI because, until recently, he served on NHGRI's Board of Scientific
Counselors for our Intramural Research Program. And, in this capacity, I can tell you that
his advice and guidance proved to be quite beneficial to our intramural investigators.
And Dr. Gibbons expects to start at NIH this summer. And we are excited to have him come
here.
For personal reasons, Chris Kaiser of MIT withdrew from becoming the new Director of
the National Institute of General Medical Sciences, NIGMS, a position he had originally
planned to begin in mid-April. As a result, Judith Greenberg will continue to act as acting
Director of NIGMS. The search to identify an NIGMS Director will begin again soon. Previously,
I served on that search committee.
And I've now been asked to co-chair that search committee along with Story Landis, the Director
of NINDS. Now, I'm willing to do this, actually excited to do it, because it's so many important
and exciting collaborative opportunities between NHGRI and NIGMS. And so I'm highly motivated
to identify outstanding candidates for this important position. So please let me know
if you have any idea of individuals that we should approach, or the search committee should
approach, of possibly becoming a candidate for this directorship.
In February, NIH launched the Genetic Testing Registry at the National Center for Biotechnology
Information. This public database aims to catalogue and disseminate information about
the availability, validity, and usefulness of genetic tests. It operates by voluntary
submissions from test providers, capturing information about intended use, target populations,
assay limitations, clinical validity, and clinical utility.
In March, the Obama administration launched the big Data Research and Development Initiative,
which aims to improve the nation's ability to extract knowledge and insights from large,
complex collections of digital data. Six U.S. government departments and agencies, including
NIH, have committed more than $200 million dollars to fund new initiatives.
The National Science Foundation and the NIH are participating in a joint solicitation
issued in March, entitled, "Core Technologies and Techniques for Advancing Big Data Science
and Engineering." Through this, NIH is particularly interested in imaging molecular, cellular,
electrophysiological, chemical, behavioral, epidemiological, clinical and other data sets
related to health and disease.
There are seven NIH institutes and centers participating, with the anticipated total
annual funding being about $3 million dollars. NHGRI anticipates contributing up to $400,000
dollars annually to this initiative.
At the February Council meeting, I reported that a working group of the Advisory Committee
to the Director, NIH Director that is, has been established to investigate the management,
integration and analysis of large biomedical data sets. This so-called data and informatics
working group, chaired by Larry Tabak, NIH Deputy Director, and David Dimetz(?) of the
University of Wisconsin, will provide the report to the NIH Director in June.
In preparation for acting on that report, three trans-NIH subgroups have been established
in the areas of molecular, phenotype and imaging data. NHGRI and NIGMS are co-leading the first
group, one focusing on molecular data. The ultimate goal is to produce a series of ideas,
internally developing them, based on information coming out of the larger working group, the
external working group, that we hope to propose as a new common fund initiative in fiscal
2014.
Recall that Francis Collins asked that a needs assessment be performed last summer by an
ad hoc committee chaired by David Ginsburg of the University of Michigan. That committee
recommended that NCBI be given special dispensation with respect to its annual budget because
of its ever-growing responsibilities to assimilate and disseminate biological data, especially
genome sequence data.
As a result, NCBI has now been guaranteed a budgetary increase each year for the next
several years, regardless of the state of the overall NIH budget. To ensure appropriate
stewardship of this unusual budgetary and programmatic situation, Francis Collins has
now established a new working group called the NCBI working group, of his advisory committee
to the Director. This group will provide advice about NCBI's services, especially with respect
to their relative priorities, in the face of conflicting demands. David Ginsberg will
also serve as the Chair of this new NCBI working group, the membership of which is shown here,
and includes council member Jill Meseroff(?).
Michael Goddesman and I will also serve on this committee in an ex officio capacity.
And recall that Michael Goddesman and I co-chair an internal group called the NCBI Resource
Board, which is responsible for helping to define the appropriate resource needs for
NCBI. Again, because of their unusual service role for the broader scientific community.
It's anticipated that this group will meet a few times a year to assess priorities, but
will also be able to give input more rapidly, if any acute issues or problems arise.
Francis Collins established the basic behavioral and social science opportunity network OPPNET
in November of 2009. The mission of OPPNET is to pursue opportunities for strengthening
basic behavioral and social science research at NIH while innovating beyond existing investments.
OPPNET prioritizes activities and initiatives that are relevant to the missions of multiple
NIH institutes and centers. All NIH institutes and centers collectively fund and manage OPPNET.
However, OPPNET is separate from the common fund. In fiscal year 2012, NHGRI contributed
about $350,000 dollars to OPPNET. Grants for the OPPNET RFA mechanistic pathways linking
psycho-social stress and behavior may come to the September Council meeting.
In terms of NIH updates, I certainly saved the best for last. The situation with the
fiscal 2013 NIH appropriation, i.e. the NIH budget for next fiscal year. Now, as you may
recall, the President delivered his proposed fiscal 2013 budget to Congress in February,
calling for essentially a flat NIH budget, relative to the current fiscal year. Congress
is now holding various hearings, including those about NIH.
So, on March 20th, Francis Collins and Tom Insel, acting Director of NCATS, testified
before the House Appropriation Sub-Committee, responsible for drafting NIH's budget each
year. There was a strong focus on NCATS and the role of NIH in translational science.
Then, on March 28th, the corresponding committee on the Senate side, held a hearing on NIH
with Francis Collins and several institute directors testifying.
Those two hearings took place in the face of some highly unusual circumstances related
to the fiscal 2013 NIH budget. For starters, we will certainly not have an agreement about
the budget until after the November election. So, whether NIH ever gets the President's
flat budget is completely unknown. We will inevitably start the new fiscal year on October
1st under a continuing resolution, meaning we will be asked to temporarily operate assuming
the same budget as the previous year.
Well, meanwhile, the elephant in the room relates to last summer's failed debt deal,
and the inaction of the not-so-super committee, which now means that an automatic eight to
nine percent budget cut or sequestration will occur in the very-- in early January, 2013,
unless some sort of new debt deal or other compromise is reached. Now, such a sequestration
is really more like a guillotine than an elephant. In fact, it's hard to even imagine how NIH
would be able to deal with such a draconian cut, especially since-- keep in mind-- it
would kick in at the 25 percent point of the fiscal year, but would be applied retroactively
to the entire fiscal year.
Well, making this particularly challenging is the November election and its uncertainties
about the next President, or the political balance in each chamber of Congress. And the
likely scenario is that we will simply not know much about the budget until at least
December and, more likely, January.
Okay. Well meanwhile, advocates are speaking out to express concerns about potential sequestration,
released on the day of the Senate hearings, a United for Medical Research report estimates
that such a budgetary cut would lead to the loss of 33,000 jobs across the United States,
which is described as a "massive step backwards for biomedical research in this country."
[off microphone]
A FAFSA(?) report released last month estimates such a sequestration would lead to a $2.8
billion dollar cut to the extramural budget, which would have a devastating effect on medical
research. While various proposed solutions are being debated in Congress to potentially
avoid a sequestration, including a recently passed House bill, it is simply hard to predict
if any of them will truly be implemented. So all we can do for now is watch and wait.
So we certainly find ourselves in a very unusual and uncomfortable circumstance, with respect
to next year's NIH budget. Between the election and the potential sequestration, it's going
to feel like a turbulent roller coaster ride for the next six to eight months. I, for one,
plan to buckle up to avoid getting tossed and turned too badly when I follow the political
news each day. And I am not routinely dosing up with Dramamine, to avoid the inevitable
nausea that will occur as things unfold.
And, just to be safe, the NIH was kind enough to install oxygen masks in the ceilings of
all institute directors' offices, which will drop down for use if the sequestration actually
kicks in. On top of it, we were all given training to be sure that we fastened the mask
on securely ourselves, before placing the mask on the faces of any of our extramural
program directors. [laughter] So, stay tuned to CNN and Genome Web for continuing developments
in this insane story.
Well, related to all this discussion about the fiscal 2013 NIH budget, but more broadly
to the turbulent ride we seem to go through every year related to budgetary uncertainties
and the lack of a long-term plan to provide the life sciences research stable annual funding,
late last week the Information Technology and Innovation Foundation and United for Medical
Research released a new report entitled "Leadership in Decline: Assessing U.S. International Competitiveness
in Biomedical Research."
This report is highly critical of the U.S.'s commitment to the life sciences, providing
evidence for our declining global leadership. The budgetary problems thrust onto the NIH
are cited as one of the core reasons for this. Included are data illustrating how a clear
picture emerges from these indicators, "The competitive position of the U.S. life sciences
industry has been eroding over the past decade."
Elsewhere they cite examples of how we are losing our competitiveness. One that hits
close to NHGRI is their point that, "China has the world's largest next generation sequencing
capacity, with more sequencing capacity than the entire United States and about one-third
of the total global capacity."
And further, the report points out, "For at least the past half century, the United States
has stood at the forefront of the global life science revolution. But amidst intensifying
global competition, continued U.S. life sciences leadership is not assured and is under clear
threat from several forces." These are all very sobering conclusions. And I strongly
urge Council members and others to download this report and really take a careful look
at it.
Well, let's move on from NIH updates to hopefully other updates related more specifically to
genomics. Starting out on a sad note, actually, Renato Dulbecco passed away this past February.
He won the 1975 Nobel Prize for his role in drawing a link between genetic mutations and
cancer. In terms of his genomics contributions and connections, in 1986 Dulbecco wrote a
heavily cited commentary in the Journal of Science entitled "A Turning Point in Cancer
Research: Sequencing the Human Genome," in which he proposed that cataloguing all human
genes by sequencing the human genome would provide the needed insights for understanding
cancer. This article was a key point, or a key part of the growing drumbeat of support
leading to the launching of the Human Genome Project in 1990.
Janet Rowley, a good friend, and many times advisor to NHGRI, was awarded the 2012 Japan
Prize in the field of healthcare and medical technology. She will share the award with
Brian Druker and Nicholas Lydon for their respective roles in development of the first
genomically targeted anti-cancer drug Gleevec.
Well known to the genomics community, David Botstein, Eric Lander, and Craig Venter were
recently awarded the 2012 Dan David Prize, given annually for achievements having an
outstanding scientific, technological, cultural or social impact on our world. Each year,
fields are chosen within three time dimensions: past, present and future. Botstein, Lander,
Venter were given their award for the future and for genomics research.
As someone who keeps a close eye on the various things going on in my hometown of St. Louis,
I'm pleased to both embarrass a Council member, but also to report that Tim Ley, Elaine Mardis
and Council member Rick Wilson of the Genome Institute of Washington University recently
received the George Englemann Interdisciplinary Award from the Academy of Sciences of St.
Louis. This new award recognizes outstanding achievements in science, engineering or technology
that results from collaboration among two or more individuals across disciplinary or
institutional boundaries. In 2008, these three researchers led the team that published a
description of the first cancer genome of a patient with acute myeloid leukemia. Congratulations,
Rick.
Recently, a number of individuals with ties to NHGRI were elected to the National Academy
of Sciences. That list included Andy Clark, Ron Dupino, Evan Eichler, Greg Cannon, Harris
Lewin and Rick Young. In addition, our good colleague and director of the National Science
Foundation, Subra Suresh, was also elected at the same time.
Bruce Corf(?) has been elected President of the American College of Medical Genetics and
Genomics, ACMG Foundation for Genetic and Genomic Medicine. He takes over for Rodney
Howe, who served as President for nine years. Bruce is currently serving on the NHGRI Board
of Scientific Counselors for our intramural research program.
As you may remember from our February Council meeting, the Presidential Commission for the
Study of Bioethical Issues has been considering bioethical issues raised by advances in human
genome sequencing. Specifically, the Commission is focusing on issues related to access to
and individual privacy protection for genetic information, with a focus on large-scale human
genome sequence data.
As part of the development of this report, the Department of Health and Human Services
published a request for information on this topic in late March, with a 60-day comment
period, as shown on the left. The Commission is also surveying federal agencies for the
relevant statues, regulations, guidance documents and policies. And I can tell you that NHGRI
staff are in close contact with the Commission staff, both to serve as a resource and to
provide input on the possible ways in which the Commission could be particularly helpful.
Comments about this effort can be submitted to the email shown there, info@bioethics.gov.
In April of this year, the life sciences marketing research firm, DeciBio, published a report
that forecasted the next few years of the life science research tools market. Although
they looked at many different research tool areas, they found that genomics is expected
to be the fastest growing segment. According to their projections, the genomic sector is
poised to grow at six percent annually over the next five years, from $6.8 billion dollars
in 2011 to $8.9 billion dollars in 2016.
Much of that growth is expected in next generation DNA sequencing, which they calculate will
grow by 16 percent each year, from $1.05 billion in 2011 to $2.25 billion in 2016. Increasingly,
the report predicts that growth in the overall life sciences research tool market will be
fueled by demand from Brazil, Russia, India and China.
Genomics is also prominently featured in the recently released White House Office of Science
and Technology Policies National Bio Economy Blueprint. This lengthy document points to
various ongoing developments in the biological sciences that will likely have important economic
impacts for the nation. Without direct input, actually, from NHGRI, they actually chose
to feature our iconic graph of the plummeting cost of genome sequencing, as shown on the
right.
It is noted that this report can actually contain very few graphics, making it particularly
flattering that the White House chose to prominently feature NHGRI's graphic. The report describes
how genomics and bioinformatics are foundational technologies, both today and for the future.
In March, the U.S. Supreme Court ended a long-running case between Prometheus Laboratories and Mayo
Medical Laboratories over a patent for determining the correct dose of a drug by looking at a
patient's blood metabolite levels. A federal district court previously found that Prometheus
was trying to patent a natural phenomenon, which the federal circuit court overturned
on appeal. The Supreme Court reached the same conclusion as the district court, finding
in favor of Mayo, who was sued by Prometheus in 2004 for offering their own tests with
slightly different thresholds for changing doses.
We're waiting to see what impact this might have on the pending case between the ACLU
and Myriad Genetics. But early signs with both diagnostics and software patent disputes
show that the lower courts are taking a stronger line on patent eligibility. However, in the
Myriad case, the lower courts have all already rejected their genotype-phenotype association
claims. This decision may not affect Myriad's isolated DNA sequence claims-- that is, claims
to purified and isolated CDNA with homology to BRCA-1 gene sequence, although the Supreme
Court's ruling does cite concern over excessive patent protections holding back biomedical
innovation. Obviously, and it always seems to be more to come in this area-- and we will
continue to aim to keep Council updated about relevant updates and developments as appropriate.
In terms of recent genomics meetings, the 2012 Advances in Genome Biology and Technology
meeting took place this past February. Once again, the demand to attend this meeting was
far greater than could be accommodated. In fact, we had a very large waiting list. And,
once again, companies queued up to unveil their latest achievements. Life Technologies
and Alumina announced the availability of new DNA sequencing machines later this year,
while Oxford Nanopore announced the availability later this year of their USB sized DNA sequencer,
the MinION.
Now, I would also point out, for those of you who couldn't go to the meeting-- and this
gives you now sort of halfway point of the Director's Report-- and I didn't want to always
let you guys believe that the only talent I have is PowerPoint. So I actually can do
other things visually. So, during breaks of the meeting, I did go out to take pictures
on the beach. Here's just a few of my photos I wanted to share with you.
This is a Caspian tern, which I learned from walking the beach, migrates from the north,
and settles in Marco Island just about the time genomists(?) show up there. [laughter]
Actually, the larger bird-- the set of birds in the back is this bird here, which is the
black skimmer, which actually migrates up from South America. And it's the largest flock
that migrates from South America and lands on the Marco Island beach every year. True
story.
My favorite are the pelicans. If you catch them in the morning, you get beautiful reflections.
Go out at lunch break, you see them flying along. And then, if you go out at sunset,
you get images like this. So okay. That was your halftime show. Back to the regular program.
[laughter]
Now you don't see beautiful things like this when you go to the Cold Spring Harbor Genome
meeting. You see other things, but you just don't see pelicans. And then, two weeks ago,
of course, there was the 2012 Biology of Genomes meeting at Cold Spring Harbor. If my memory
and my arithmetic are correct-- but someone can correct me if I'm wrong-- I think this
was the 24th annual Cold Spring Harbor Genome meeting, as they're called. And Rick's doing
the calculation, because I know he was probably at the very first one.
Notable highlights from this meeting included several talks on single cell genomics, impressive
updates on cancer sequencing projects, and an LC panel discussion on genomic literacy.
And then, finally, keynote presentations by Debbie Knickerson(?) and Susan Wesler. Am
I right, Rick, 24? Is that what you think? I think it's 24. Keep calculating.
A NOVA special, entitled Cracking Your Genetic Code debuted on PBS stations in March. The
development of this show was in part funded by NHGRI. And numerous familiar faces were
featured throughout the one-year-- throughout the one-hour program. The show examines the
evolving genomic technologies and research surrounding genetics and genomics-based medicine.
NHGRI continues to feature a genome advance of the month on our website, Genome.gov. Two
recent publications that were featured since the last Council meeting reported population
level characteristics of loss of function variants in the human genome in a personal
o-mix(?) profile approach to personalized medicine.
Speaking of regular features, let me move on to my regular genomics in the news portion
of my Director's Report, also filled with notable stories and maybe a little bit of
fun-- at least I have fun with it. We'll start with something more serious, because it involves
a Council member.
Council member David Kingsley and colleagues at Stanford University and the Broad Institute
analyzed whole genome sequences of 21 three-spined sticklebacks chosen from geographical locations
around the world. The findings, which appeared on an excellent paper published in Nature
in April, are helping to identify the regions of the stickleback genomes responsible for
notable phenotypic adaptations.
Meanwhile, Nature also recently published a paper reporting the genome sequence of the
gorilla, an effort involving a consortium of investigators, including researchers at
the Sanger Institute and Council member Rick Wilson. While confirming that our closest
relative is the chimpanzee, the team found some interesting results pointing to many
regions of the human genome that more closely resembles the gorilla than the chimpanzee
genome.
Three papers reporting new findings about the genetics of autism were published in Nature
last month, representing the work led by Evan Eichler, Mark Daly and Matthew State. Whole
genome sequence or whole exome sequencing was performed by all three groups, unveiling
interesting patterns of gene mutations in autism. The result suggested modest roles
for hundreds of genes in the development of autism and pinpointed a few specific genes
as genuine risk factors.
These findings were reported in the New York Times in an article that included this photograph
of Evan Eichler, Jay Shendure, and Brian O'Roak of the University of Washington.
The Colbert Report has recently become the place to catch up on the latest advances in
genomics and science in general. I don't know if that's good or bad. It's just what it is.
David Page was recently a guest on The Colbert Report, where he used creative props to discuss
the evolution of sex chromosomes. David was, for the most part, in control of the interview
when he had the model chromosomes in his hand. But all hell broke loose when Colbert got
his hands on a chromosome.
Not to be outdone, Francis Collins appeared on the show two weeks ago for his third appearance
going toe-to-toe with Colbert. In this case, he talked about obesity and the new multipart
HBO series called Weight of the Nation. Francis brought with him a five-pound model of fat.
Once again, once in Colbert's hands, Colbert couldn't keep his hands off the scientific
prop.
And finally, genomics in the news. In early April, NPR ran this story about a preschool
academy in New York City, reporting that this school, that will now require submission of
a DNA sample for each child as part of their application. DNA testing would then be performed
as part of the evaluation process of that child, "in order to weed out the kids who
have no chance."
As one might imagine, the story had the potential to bring significant distress and debate in
the genomics community. But, before LC researchers and genomic activists around the world had
a chance to self-organize and protest, NPR admitted that this story issued on April 1
was just an April Fool's joke. [laughter]
Okay. Moving on to the extramural program. It seems--
MALE: That wasn't funny, Eric.
ERIC GREEN: It wasn't funny? So write to NPR.
[off microphone]
Oh, that's probably true.
[off microphone]
ERIC GREEN: See it's always better if it's on Colbert, right, because-- Okay.
Moving on to the extramural program, it seems appropriate to start with our genome sequencing
program. We recall that there's four components of the recently renewed NHGRI genome sequencing
program. Large scale genome sequencing centers, Mendelian disorders genome centers, clinical
sequencing exploratory research projects, and informatics tools for high throughput
sequence data analysis.
Each of these programs we discussed further in subsequent slides. But I want to note that,
for the first time, all four components of our genome sequencing program will get together
for a face-to-face meeting in October. In addition to the necessary housekeeping tasks,
we hope that the attendees will use this opportunity to pursue shared goals, discuss common obstacles,
and engage directly with their mutual scientific objectives.
Starting off first with the large-scale genome sequencing centers, who are undertaking numerous
projects, mostly related to complex disease and cancer. Notably, in February, the Obama
administration announced new efforts to fight Alzheimer's disease, including make an additional
$50 million dollars of existing NIH funds available for cutting-edge Alzheimer's research.
Accounting for half of those funds, the large-scale genome sequencing centers program is in the
late planning stages for a significant Alzheimer's disease genome sequencing project in collaboration
with the National Institute on Aging and its grantees.
Also worth noting are highlights that point to a number of publications emanating from
these centers since the last Council meeting, including those related to autism, schizophrenia,
cancer, comparative genomics, and population genomics.
Additional highlight is appropriated in the case of The Cancer Genome Atlas, TCGA, which
involves our large-scale genome sequencing centers. TCGA has been hard at work on about
20 different tumor types and has papers in press or under review that report analyses
for three major diseases: colorectal carcinoma, breast carcinoma, and lung squamous cell carcinoma.
Each of these projects will continue to the TCGA practice of releasing the largest scale,
in terms of hundreds of tumors, and most comprehensive descriptions to date, in terms of mutations,
copy number changes, gene expression, methylation and clinical data for each of these important
cancers. Several additional manuscripts are also anticipated this year from TCGA.
And then, in other TCGA news, CG Hub, the new TCGA sequence data repository developed
at UC Santa Cruz, recently opened. CG Hub is now the site that investigators can find
all TCGA primary sequence files. Throughout this year, CG Hub anticipates adding new features
to make these data more useful, such as being able to slice bands, the very large files
containing sequence from a normal or tumor sample, so that an investigator can download
only a particular gene or genomic region, rather than the entire genome sequence.
In a non-trivial advance on the policy front, CG Hub is the first NIH trusted partner for
archiving and distributing genome sequence data outside of NCBI or EBI. Several more
trusted partners for NIH projects are being developed. These will each add value to this
type of data and make them more useful and accessible to investigators. TCGA continues
to be on target for its ambitious goal of completing comprehensive analysis of greater
than 20 tumor types by 2014. Genomic data on greater than 6,000 cancer cases are available
now with approximately 200 added to the data portal each month.
The second component of NHGRI's new genome sequencing program consists of the Mendelian
Disorders Genome Centers. The Three Centers for Mendelian Genomics, as they are called,
are co-funded by NHGRI and NHLBI. And they aim to discover the genetic basis for as many
Mendelian disorders as possible. The program's single sample solicitation web portal has
gone live. And a pipeline has been implemented, shown here, that progresses from solicitation
through sample assignment at the centers, that are at Yale, Baylor Hopkins, and the
University of Washington. The pipeline is jointly run by the three centers, with the
University of Washington coordinating all joint activities.
The centers have organized an educational program focusing on Mendelian genomics that
will be held at the 2012 Annual Meeting of the American Society of Human Genetics. And
disease gene discovery is ongoing at the centers at various stages, from sequencing to the
identification of disease genes.
The third component of NHGRI's new genome sequencing program consists of the clinical
sequencing exploratory research projects. The steering committee for this program, called
CSER, held its first face-to-face meeting a few weeks ago, a gathering that occurred
jointly with the LC program's new return of results consortium. The CSER investigators
are tackling the important regulatory, technical and psycho-social challenges to bringing genomic
medicine to patients.
Discussions at the meeting emphasized critical topics, such as informed consent, refining
definitions of actionability, distinctions between clinical care versus clinical research,
and success stories from early implementation of clinical sequencing. Several of our Council
members attended this meeting: Jim Evans, and Amy Maguire, as investigators in the program,
and Pamela [01:27:27] representing the Sequencing Advisory Panel.
In addition to the first meeting, there was a great response to the original solicitation
for the CSER program. So we've now reissued the RFA. It is in the NIH guide, now, with
an application of receipt date of July 26th. Accompanying the reissue is also an RFA for
a coordination center for the program which will support the CSER program and the return
of results consortium, in addition to contributing to the assimilation and distribution of best
practices and empirical evidence for this rapidly advancing area.
The fourth and final component of NHGRI's new genome sequencing program consists of
grants to support the development of informatics tools to high throughput sequence data analysis.
Investigators are now using DNA sequencing instruments that are as powerful as an entire
genome center was just a few years ago. But only the first step of DNA sequence production
can be purchased "in a box." Investigators are not able to buy bio informatics center
in a box to make sense of the resulting data. And that then represents the challenge that
this program is attempting to address.
The network of grantees funded as part of the fourth component of our sequencing program
has chosen a name to reflect its mission: IC Tools, which the aim of this network is
to develop robust and reliable analysis tools for use by researchers without specialized
computational skills. For this program is an effort to leverage NHGRI's considerable
investment and sequencing centers, as well as initiatives such as 1000 Genomes, Galaxies
and others. A catalogue of tools and strategies is being assembled on the IC Tools Wiki to
create a knowledge-base and to identify synergies.
The DNA Sequencing Technology Development Program held its eighth annual grantee meeting
in early April. The meeting was attended by130 members of grantee laboratories. And they
were then joined for an additional day by 40 others, who were interested in developing
technologies for faster, less expensive, and more accurate DNA sequence generation.
Participants heard updates on technology innovations that ranged from how higher quality and longer
reads using currently available instruments to better understanding how DNA molecules
are captured by and interact with nanopores, to approaches for better fabricating and recording
from solid state DNA sequencing devices.
The highlight of the meeting was presentation of two papers published on the second day
of the meeting, papers that were featured on the cover of the April issue of Nature
Biotechnology. These papers demonstrated reproducible electronic signals corresponding to the sequence
of DNA molecules translocating through a nanopore. This progress represents the end of a 20-year
odyssey since the idea was first proposed in1992.
And it's exciting that the three people who conceived of this approach for sequencing
DNA were all at the meeting. Daniel Branton, David Deimer(?), and George Church. The actual
papers were published by the Laboratories of Jans Gundland (?) and Mark Eicheson(?)
and several of the members of these groups were also at the meeting. While this represents
the end of an odyssey, in a very real sense, this is just the beginning of a journey, with
the first commercial device that uses nanopores for sequencing DNA expected to be available
commercially later this year. And many opportunities on the horizon, to turn this remarkable scientific
progress into robust, more accurate, faster, and inexpensive DNA sequencing technologies.
Moving on to NCode and Mod (?) NCode, ten NCode Technology Development Awards were funded
in April. And an 11th award is expected to be funded in May. These projects aim to develop
improved methods for identifying functional elements and for validating their biological
function. Meanwhile, three NCode RFAs were released in October of the past year. And
applications were received in December. These RFAs aimed to support research projects that
applied high throughput, cost-efficient approaches to extend NCode resources towards as complete
a catalogue as possible. These applications will be discussed by Council in the closed
session.
NHGRI is organizing a mod NCode symposium to be held in the Natural Conference Center
on the NIH campus on June 20th and 21st. The symposium is open to the public, and registration
is encouraged. The meeting is planned to tie into the Genetic Society of America meeting
entitled Model Organisms to Human Biology Cancer Genetics, which is scheduled to take
place in Washington, D.C. from June 17th to 20th.
There are various integrative analysis papers being planned. The NCode consortium has a
main integrative paper and many companion papers currently under review, with publication
expected to occur in the early fall. The Mod NCode and NCode consortium are currently working
to integrate worm, fly and human NCode data. And the mouse NCode consortium is currently
planning a comparison of human and mouse data.
Moving on to the LC program, the LC program issued two RFAs in connection with its Centers
of Excellence or SEAR(?) program, a P20 RFA to fund up to two exploratory centers, and
a P50 RFA to fund up to two additional full centers. These applications are due in July
for review in the fall, with funding after next February's Council's meeting.
The LC program formally launched its return of results consortium, which consisted of
investigators on R01 and R21 projects funded through RFAs focused on this topic, as well
as investigators involved in the Ethical and Psycho-Social Research components of the Clinical
Sequencing Exploratory Research Program that I spoke of earlier. And several others, with
investigator initiated projects, studying issues related to this important topic.
And, as I mentioned already, the consortium recently held its first face-to-face meeting,
in conjunction with the CSER steering committee. Working groups have been established, dealing
with instruments and measures, informed consent, actionability, and special issues related
to returning results in the pediatric context.
The April, 2012 issue of Genetics in Medicine focused on issues relating to return of results
in incidental findings. A large number of the papers in that issue are the result of
research funded by our LC program. And many of the authors are members of the new consortium.
In terms of upcoming planning meetings, there's just one that is worth mentioning at this
time, an NHGRI workshop on integrating functional data for connecting genotype to phenotype
will be held July 30th and 31st. This meeting seeks to explore more deeply some ideas that
came out of planning efforts in the area of basic genomics. Specifically, the workshop
will address whether there are some practical systematic way to comprehensively bridge the
gap between sequence and phenotype, by producing a catalogue of multilevel functional annotations
of all genomic elements.
The workshop will also discuss the utility of potential data types, organization of the
information and integration relative to both translation and the understanding of basic
biology.
So, moving on to the NIH common fund, where, as always, NHGRI has extensive involvement,
starting off with the human microbiome project. I will point out that funding for the human
microbiome project ends this fiscal year, in fiscal 2012. Two major publications of
the HMP Consortium have been accepted by Nature and will be published in June. The first describes
the community resources developed by HMP. The second is a metagenomic analysis of the
300 subject healthy cohort involving five body sites.
The latter study focused on the structure and dynamics of the microbial communities
and, on analysis of the metabolic capabilities of the microbiomes through an in silica reconstruction
of metabolic pathways. These two papers will be accompanied by the release of over 20 companion
papers in a plus virtual "HMP collection."
Over the last four months, meanwhile, a working group of program staff, representing 12 NIH
institutes and centers, developed a proposal for a follow-on program to HMP. The proposal
for a so-called HMP 2 was submitted to the common fund in April and is currently being
evaluated. A full report about HMP and a possible HMP 2 will be given at the September Council
meeting.
The knockout mouse phenotyping project, or COMP 2, is the second phase of an initiative
that aims to create a public resource comprised of mice containing a known mutation in every
gene in the mouse genome. In five years, COMP 2 aims to make 2,500 live mouse strains from
knockout ES cells. COMP 2 awards were made in fiscal 2011, with overall funding for the
program being $111 million dollars over five years.
Three centers proposing paired mouse production and mouse phenotyping applications were ultimately
funded. Final operating protocols for comprehensively phenotyping the knockout mice strains have
been approved and adopted. And, in order to make data in mice available to researchers,
an application was funded for a data coordination center and database at EBI. The center is
now housing a website that will be actively updated to show status and to eventually display
the phenotypic data.
COMP 2 has committed to collaborate with other international projects to achieve a total
of 5,000 phenotype strains through the International Mouse Phenotyping Consortium, otherwise known
as the IMPC. The IMPC now includes nine active programs. And COMP 2 will be holding joint
coordination meetings with this consortium.
Moving on to the Genotype Tissue Expression project, the pilot phase of GTEX has been
very successful meeting the project's goals, in terms of enrollment and RNA quality. For
example, the project has averaged greater than 10 donors a month, with over 130 post-mortem
donors enrolled thus far. RIN values, which are a measure of RNA quality, have been very
good, with the RNA from more than a dozen organs having a RIN value of greater than
six for more than 70 percent of the cases. Preliminary gene expression results look quite
good. In fact, they look great.
The common fund is now considering a scale-up proposal to enroll and study a total of 900
donors with a decision expected soon. The first DB gap data release, which will reflect
a March data freeze for this project, is expected later this month.
The LINKS program will hold its annual consortium meeting in November. Members of the data generation
computational center and technology development groups are expected to attend, as well as
the program's external scientific panel. The NIH staff overseeing LINKS made a request
to the common fund for a one-year extension of the pilot through the provision of a fiscal
2013 bridge funds. If approved, this would allow for more robust development of a plan
for a LINKS phase two, starting in fiscal 2014.
Acting on a recommendation of its external scientific panel, LINKS has established a
schedule for the quarterly release of data starting this past fall, starting this past
March. Also, NIH staff is currently finalizing language for a LINKS data release policy.
The protein capture reagents program is maintaining communication through several newly developed
working groups, those focused on data dissemination, validation, and target list prioritization.
These working groups are chaired by program investigators. They meet regularly and have
made significant progress towards the program capture reagents program and its objectives.
As part of the target list prioritization working group, members are seeking community
input on priorities for producing human transcription factor reagents. Input will be taken, starting
June 1st and ending July 31st. The program will then evaluate responses based on rationale
and significance. This working group has already collected input from the NCODE consortium
and various other external groups.
The H3Africa project received 57 applications from across the African continent, in response
to the first set of RFAs. These applications were reviewed in March and April. A funding
plan based on these reviews will be discussed during the closed session of this Council
meeting after which a small group of NIH staff will make site visits to the potential grantees.
Finally, the inaugural H3Africa Research Network meeting will be held in Ethiopia in October,
jointly hosted by the Welcome Trust, our partners for H3Africa.
Single cell analysis is a new common fund program with the goals of, one, analyzing
general principles of cellular heterogeneity via transcriptional profiling; two, establishing
a quantum leap in spatial/temporal resolution within tissues; and three, pursuing extensions
in applications in the clinic. Three RFAs were issued, one for each of these areas.
And the submitted applications were reviewed earlier this month. In addition, a workshop
for this initiative was recently held that focused on identifying gaps and opportunities
in single cell analysis.
NHGRI has particular interest in this program for several reasons. First, we're interested
in new technologies that might emerge, since we have historically supported awards that
aim to perform DNA sequencing at the single cell level. Second, we have an interest in
understanding networks and pathways generated from genomic data, and understanding the role
of cellular heterogeneity at the single cell level will be crucial for this. And finally,
there is potentially the opportunity for advancing clinical applications of genomic technologies
that focus on single cells through this initiative. So programmatically, we will be involved in
making funding recommendations, and we can participate in the managing the grants of
this common fund project.
So that's what I wanted to tell you about common fund. Now, moving on to the Office
of the Director, starting off with the Office of Population Genomics. In March, the eMERGE
Network released its online phenotype library and tools, a tool called PheKB(?). This is
a knowledge base for discovering phenotypes from electronic medical records. The purpose
of this is to provide a collaborative environment for building and validating electronic phenotype
algorithms. There are now 17 phenotype algorithms in PheKB, including atrial fibrillation, cataracts,
Crohn's disease, type 2 diabetes, diabetic retinopathy, hypothyroidism, and so forth.
And currently, it has the following functions. It allows you to view existing algorithms,
to enter or create new algorithms, to collaborate with others to create or review algorithms,
or to review implementation details of existing algorithms.
Also related to eMERGE, on behalf of the eMERGE Consortium, Bradley Mallon(?) recently presented
testimony to the National Committee on Vital and Health Statistics, or NCVHS Subcommittee
on Privacy, Confidentiality and Security. NCVHS is a major advisor committee to the
Secretary of the Department of Health and Human Services. Brad presented the eMERGE
experience in developing, applying and evaluating policies and technologies for the governance
of electronic medical record systems and bio banks through a lifecycle of data management.
This included insights about data collection, community engagement models, community advisory
boards, and promotion of research to the community, data utilization, an overarching data use
agreement for sharing data in the consortium, and data dissemination, to identify data submitted
to DB Gap for data sharing beyond the eMERGE sites.
Moving on to GENEVA, the Gene Environment Association Studies, GENEVA initiative reaches
its conclusion at the end of this month, May. 20 data sets that have been posted to DB Gap
for a wide variety of phenotypes, all of which have been imputed to a standard 1000 Genomes
reference. Overall, GENEVA investigators have produced more than 50 publications since 2009.
And further, they developed a bioconductor software package called GEWIST Tools for cleaning
and analyzing GEWIST data.
Turning now to Phoenix, progress continues in the growth of the Phoenix toolkit. Most
recently, the National Institute of Drug Abuse, NIDA, provided funds to expand the toolkit
to include additional substance use measures. In February, 43 new measures related to substance
use and addiction were added to the Phoenix toolkit. The inclusion of these measures resulted
from a year and a half-long collaboration between NHGRI, NIDA, and the Phoenix Project
team.
The Phoenix team used a consensus-based process to select and vet measures that involved content
experts in NIDA's extramural research community. A substance abuse and addiction scientific
panel was convened to oversee the process. And three expert working groups identified
measures and addressed substance use and related intermediate phenotypes, cognitive and psycho-social
risk factors, and community comorbidities and health-related outcomes. NIDA, meanwhile,
is encouraging all grant applicants proposing human subjects research to use the Phoenix
toolkit to increase research stability to combine studies and gain the much needed statistical
power to identify genes related to substance use and addiction.
Moving on to other parts of the Office of the Director, the complete collection of articles
on genomic medicine have now been published as part of the New England Journal of Medicine's
series edited by Greg Fiero, who I mentioned earlier, and also Alan Gutmacher(?). Shown
here is the last article, as well as a closing editorial, both published since the last Council
meeting.
The NHGRI DNA day chat room has been an annual event since 2005. This year, the chat room
was held April 20th for nine hours. And was staffed by more than 70 experts from around
the country. In total, we received more than 900 questions, of which 764 were answered.
Questions were received from students from 37 states and outside of the United States.
The states sending in the most questions were Indiana, Pennsylvania, California, Georgia
and Nevada. The majority of questions received were from ninth graders, although there was
a significant number of middle school students submitting questions as well.
The second annual USA Science and Engineering Festival took place in April at the Washington
Convention Center in DC. As with the last festival held in October of 2010, NIH was
there in force. And NHGRI was among the most involved institutes. This year, we also partnered
with the American Society of Human Genetics on joint activities. In total, more than 25
volunteers from NHGRI participated.
Shown here-- when it comes up-- is an aerial view of the convention center floor, where
most of the NIH booths were located. This is the area on the convention floor where
NIH was heavily represented, most of which had hands-on activities. Not surprisingly,
NHGRI's booth was packed with interested learners all day, every day. Our activity, of course,
was to purify DNA from strawberries. This made many children very happy. But it did
mean that 20 pounds of strawberries sacrificed their cellular existence in pursuit of purified
DNA.
And then on the second day, we actually ran out of strawberries. So shown here is my 12
year old daughter, Abby, frantically working with the fruit DNA purifying extraordinaire
and booth czar, Carla Easter, of course, to see if they could quickly get a protocol involving
bananas to work, having unexpectedly run out of strawberries. So, following a bit of onsite
optimization, a revised protocol emerged. And booth visitors were able to purify small
amounts of DNA from hunks of banana stolen from people's box lunches. [laughter]
NHGRI is collaborating with Suburban Hospital in Bethesda and the Johns Hopkins University
School of Medicine to hold a monthly grand rounds style seminar, covering topics in genomic
medicine. Greg Fiero is leading the planning committee for this series. Talks are being
held on the first Friday of each month, with the next one being given by Barb [01:47:22]
in early June.
We have just invited the next slate of speakers listed here, who will give talks starting
in July, running through next January. But of particular relevance-- and the reason why
I really want to point this out to Council-- is that all these talks are being videotaped
and made available on NHGRI's genome TV channel of YouTube.
And finally, moving on very briefly to the intramural program, there are some recent
highlights from NHGRI's intramural research program that include, for example, Charles
Rotimi(?) and colleagues in the Center for Research on Genomics and Global Health, who
published a study in the New England Journal of Medicine identifying genetic association
between the HLA Class 2 locus and the tropical disorder podoconiosis. This condition affects
four million people in ten poor countries.
And K.J. Monk(?) reported in [01:48:13] National Academy of Sciences paper, the development
of molecular screen that detected 22 DNA damaging antioxidants. These compounds were shown to
be lethal to dividing cells, such as those in tumors.
NHGRI recently completed the 10th iteration of its very popular lecture series called
Current Topics in Genome Analysis, which Andy [01:48:34] and I started as an educational
outreach effort of NHGRI's intramural research program back in the mid-1990s. In recent years,
we have moved to posting the videos and PowerPoint presentation from these lectures to our genome
TV channel of YouTube. And the viewership has been truly phenomenal.
For example, there have been over 20,000 views of these lectures from our recently completed
series in 2012. But this number will only grow substantially if things play out, as
in previous years, and as a data point. You see, for example, the last iteration of the
series back in 2010 resulted in over 200,000 views of the lectures. And I can tell you,
I routinely hear about interest in watching this lecture series of the archive videos,
especially when I travel abroad.
And finally-- and I mentioned this in previous council meetings-- the NHGRI intramural research
program is currently undergoing a blue ribbon panel review, the last one being in 2001,
which is supposed to be done every 10 years. And shown here is the panel's membership.
And note that Rick Myers is the representative from Council. The blue ribbon panel review
will be completed this summer.
And, as a result of the September Council meeting, we're going to have two things related
to this. First of all, you will get, for the first time, a general presentation about the
NHGRI intramural research program from Dan Caster(?), recently appointed Scientific Director,
who directs our Division of Intramural Research. He'll give a general overview about the intramural
program.
And then second, a formal presentation about the blue ribbon panel's review and their report
will be given by Rick Myers.
And with that, I am done. And as always, I want to give a special thanks to Chris Waterstrand(?)
who is the key person coordinating all of this material coming in Director's Report,
but also to Larry Thompson, Judy White, and the NHGRI team for helping the electronic
aspects of this.
This is the picture I always show of Chris. But the other thing that's important, that
happened since the last Council meeting, is that Chris took a once in a lifetime trip
to the Galapagos Islands. And so, shown here in the background-- you've got to figure out
what bird that is, Jim Evans. You're the one that might know it. That is a red-footed ***
chicklet, or a little -- not adolescent kind of bird, red-footed *** behind Chris Waterstrand
in that picture. And I'm sure, if you asked her at our break, she'll show you hundreds
of pictures. [laughter]
So with that, I will stop and happy to take any questions you have.