Genome Technology

Contents | Zoom in | Zoom out For navigation instructions please click here Search Issue | Next Page This Month in Genome Technology

SPECIAL ISSUE Genome Technology GT Celebrates the Rising Young Stars of Science 30 promising researchers – recommended by today’s established PIs – are proﬁled in this exclusive year-end issue. We highlight their work in these categories and more: Sequencing Synthetic biology RNAi Gene expression Computational biology Structural variation Proteomics Translational research Genome Technology Online Log on now at www.genome-technology.com Recent results from GT Polls Explore all of our exclusive new resources for molecular biologists: Would you speak at a conference that The Daily Scan: Our editors’ daily picks of what’s worth reading didn’t pay your registration fee? on the Web. Nope, I’d boycott on principle. They should The Forum: Where scientists can inquire and comment on at least let you into the conference. 66% research, tools, and other topics. I’d grumble about it, but ultimately accept. Podcasts: Hear the full comments – in their own voices – of It’s worth the extra line on my CV. 16% researchers interviewed in the Genome Technology Magazine. Sure, why not? 18% Polls: Make your opinion known on topics from the sublime to the ridiculous. Archive: Magazine subscribers can read every word of every article we have ever published.

______

9FELJ1 NEXT-GEN SEQUENCE ANALYSIS AND AGBIO TECH GUIDES

;<:

______

DECEMBER 2008/JANUARY 2009 Contents

28 CARL KINGSFORD A computer Tomorrow’s PIs scientist takes on transcription Resources SEQUENCING 29 JAMES TAYLOR 5 PRIMER Researching to help researchers Starting out, already stars 9 JAY SHENDURE Functional testing with next-gen technology 30 WOLFGANG HUBER 7 DEMOGRAPHICS Pushing statistics to the limit In numbers 10 LI DING The genomic basis of cancer PROTEOMICS 48 CAREERS Steps to start your career 11 ROBERT RIEHN Stretching 31 XUDONG YAO From signal and sequencing DNA transduction to cystic ﬁbrosis 51 FUNDING Grant opportunities SYNTHETIC BIOLOGY 32 GISELLE KNUDSEN From detection to drugs 53 LOOKING AHEAD 12 TIM LU Letting the bedside Next-gen tomorrow’s PIs inform the bench 33 WEI-JUN QIAN Step by step, a better mass spec 54 CLASS OF 2007 STRUCTURAL BIOLOGY A year later POPULATION GENETICS 15 DAVID MATHEWS Looking for 57 RECOMMENDERS Thanks to today’s PIs secondary structure 34 SHAMIL SUNYAEV A better approach to interpretation 16 BOJAN ZAGROVIC 58 BLUNT END Finding order in disorder 35 RAUL RABADAN Elucidating evolution, virus by virus 17 OLIVER RANDO Opening the ‘black box’ of chromatin COMPARATIVE GENOMICS RNA INTERFERENCE 37 RACHAEL THOMAS Cancer in dogs, cats, and people 19 JULIUS BRENNECKE Parsing nature’s elegant solutions TRANSLATIONAL 20 KEVIN MORRIS RESEARCH “In the future, Another mode of gene silencing 39 CAREY LUMENG Investigating experimental and the perils of obesity STRUCTURAL VARIATION computational 40 BRIDGET WAGNER Large-scale 21 GREG COOPER screens to study diabetes biology are only going A compelling look at variation 41 CHARLES SCHROEDER to become more GENE EXPRESSION ‘Cells in, disease out’ intertwined and even 23 ADRIANA BRISCOE 42 GAD GETZ The physicist who inseparable. What I It’s all in the eyes tackled cancer hope to see is a culture 24 UWE OHLER Imaging gene regulation REGULATORY ELEMENTS that ... [understands] 45 LEN PENNACCHIO Finding 25 MARIAN WALHOUT A fresh look if it isn’t transparent function in dark matter at differential expression and reproducible, it 46 ZHAOLEI ZHANG Where COMPUTATIONAL BIOLOGY collaborations are king isn’t science.” 27 PAUL FLICEK 47 LAURA ELNITSKI In the informatics trenches The functional perspective James Taylor, page 29

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 3

______

FROM THE EDITOR Primer

ISSUE NO. 87 125 Maiden Lane, Second Floor New York, NY 10038 Starting Out, Already Stars Tel +1 212 269 4747 Fax +1 212 269 3686 GENOME-TECHNOLOGY.COM______ack when we came up with the idea for Tomorrow’s PIs EDITORIAL DIRECTOR — a special issue designed to introduce our readers to a Meredith W. Salisbury new generation of promising scientists still early in their [email protected] SENIOR EDITOR careers — we really had no clue how the whole thing Ciara Curtin [email protected] would pan out. Now, as we’re getting ready to send the SENIOR WRITERS Bthird annual Tomorrow’s PIs edition to the printer, we can’t imagine Matthew Dublin [email protected] Jeanene Swanson [email protected] what we’d do without it. People we’ve profiled in the past have gone ART DIRECTOR Therese Shechter ______info@trixiefilms.com on to do great things in science, and no doubt that will continue. GENOMEWEB DAILY NEWS This magazine began in the summer, when we started consulting Bernadette Toner, Editorial Director, News experts in the systems biology community to get recommenda- [email protected] tions for scientists who will soon be taking the world by storm. We Ed Winnick, Managing Editor [email protected] looked for nominees who are no more than five years or so past their Matt Jones, Reporter postdoc and then selected a group with a diverse range of scientific [email protected] interests, backgrounds, and affiliations. After many, many inter- Andrea Anderson, Reporter [email protected] views (and more planning meetings than the Genome Technology staff GENOMEWEB NEWSLETTERS would care to remember), we emerged Kirell Lakhman, News Editor [email protected] with the final 30 people who are profiled Justin Petrone, BioArray News Editor in this issue. As always, we had far more [email protected] recommendations than we could actually Vivien Marx, BioInform Editor [email protected]______print, so we’ll have mini-profiles of many Alex Philippidis, BioRegion News Editor more young investigators throughout the [email protected] year at www.genome-technology.com. Ben Butkus, Biotech Transfer Week Editor [email protected] We’re so grateful to the outstanding Charlotte LoBuono, Cell-Based Assay News Editor [email protected] cast of scientists who contacted us with Julia Karow, In Sequence Editor nominations — without them, this issue [email protected] would not be possible. Turna Ray, Pharmacogenomics Reporter Editor [email protected]______One thing we noticed this year was a particular challenge in as- Tony Fong, ProteoMonitor Editor signing these up-and-coming scientists to technology categories. The [email protected] research they’re engaged in is becoming more integrative, bringing Doug Macron, RNAi News Editor [email protected]______together lots of platforms and concepts from different disciplines. CHAIRMAN AND PUBLISHER You’ll also see that next-gen sequencing is really shaking things up; Dennis P.Waters, PhD [email protected] many of the scientists say that advances in that technology have ADVERTISING/SALES thoroughly changed the kinds of experiments they’re able to do. Judy Block, Associate Publisher The advertisers in this issue have made it possible for us to give [email protected] +1 212 651 5629 a travel stipend to each of the scientists profiled here, so we also Allan Nixon, Director of Business Development [email protected] +1 212 651 5623 thank them very much for their generosity and support of these David Samuels, Subscriptions and early-career researchers. Site License Manager [email protected]______OPERATIONS AND FINANCE Greg Anderson, Director [email protected] Meredith W. Salisbury, Editor Philip Borowiecki, Associate [email protected]

What do you think of Genome Technology? Let me know how we’re doing by e-mailing me at [email protected] or by calling me at +1.212.651.5635

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 5

______

In Numbers Our bunch of young investigators is an accomplished group. Here is a smattering of what they have accomplished and where. Stanford University 26 Most common PhD institute Number of Nature papers 11 years Longest time since PhD: 13 Shamil Sunyaev and Marian Walhout, 1997 Number of Science papers This year 2 Shortest time since PhD: Tim Lu HHMI pre-doctoral fellows Boston 6 Most common current metropolitan area Investigators with NHGRI funding Massachusetts, Washington, Maryland 4 Most popular locations for recommenders MD/PhDs 4 Recommenders are current HHMI Investigators: James Collins, Evan Eichler, Stuart Schreiber, 8 Phillip Zamore Number of PhDs from non-US institutions 10 1 Number who say that next-gen sequencing has Recommenders who won the Lasker Prize this changed their work year: Victor Ambros

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 7

______

Jay Shendure SEQUENCING

Functional Testing with Next-Gen Technology

any in the sequenc- Looking ahead ing world may already be famil- Peering into his crystal ball, Shen- Miar with Jay Shen- dure predicts that five to 10 years dure, the young investigator who, down the line, he and everyone else along with his colleagues in George involved in life sciences research will Church’s lab, helped to pioneer be able to sequence virtually any- polony sequencing, a highly paral- thing in a cost-effective and feasible lel, low-cost sequencing method. way. Shendure says the ability to Now, Shendure’s lab continues to accurately predict function from a se- advance technical elements related quence in a robust and accurate way to sequencing — specifically in would help speed things up as well. areas of experimental methods and “This is something that’s extremely computational tool development, in- difficult, but that certainly would cluding platforms for array-based, be nice to have,” he says. “It would programmable DNA synthesis and be great if we’re building things, if massively parallelized, short-read we’re synthesizing things, to be able DNA sequencing. TITLE: Assistant Professor of Genome to predict what they’ll do, but also, Shendure has also been instrumen- Sciences, University of Washington looking at variation in the human tal in developing a method to selec- EDUCATION: PhD, Harvard University, genome, to know what that does as tively capture all the protein-coding 2005; MD, Harvard Medical School, well.” sequences with a microarray as a 2007 sample prep approach to next-gen RECOMMENDED BY: Publications of note sequencing. His lab continues to Alan Guttmacher, Mary-Claire King work on aqueous-phase and solid- In the paper “Accurate multiplex phase protocols to capture genomic polony sequencing of a bacterial ge- subsets. cis-regulatory elements. So far, they nome” published in Science in 2005, The Shendure lab is also check- have been able to demonstrate this Shendure, Church, and their col- ing out experimental methods approach on well-characterized bac- leagues outline their use of off-the- that would enable de novo genome teriophage promoters, he says. shelf instrumentation and reagents sequencing using next-gen technol- It probably goes without saying that to perform polony sequencing. The ogy. “A growing interest [is] in syn- Shendure’s time in George Church’s authors describe resequencing an thetic aspects — more specifically, lab left an indelible mark on his ap- evolved strain of E. coli at less than how you use off-array synthesis of proach to science. “I think it’s one one error per million consensus oligos in other ways, such as trying of these rare places where there are bases using a method to convert to create long synthetic constructs all kinds of those people around — an epifluorescence microscope into a that can be used for various things,” biologists, physicist, engineers, all nonelectrophoretic automated DNA he says. “The particular thing we’re in the same working group — and sequencing platform. interested in is developing very high- also just the tremendous amount of throughput means of doing func- creative freedom and flexibility very And the Nobel goes to... tional testing of variants.” early in your career to do whatever While there is currently a lack of experiment you want to do,” he says. Shendure says that if he were to be quantitative models for defining cis- “George never told me I couldn’t do an awarded the Nobel prize, he would regulatory elements, Shendure and experiment, no matter how outlandish like it be for something contributing his team are developing a platform it was. It was always my choice, and I to world peace, rather than any sort for high-throughput screening and think having that sort of freedom very of technical innovation. high-resolution functional analysis of early on was a good thing.” — Matthew Dublin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 9

Li Ding SEQUENCING

The Genomic Basis of Cancer

ancer is a disease of genes son and Mardis suggested looking at and of pathways, says Li more samples even more deeply and Ding, a researcher at the going back to older data to figure it Cgenome center at Wash- out. “They will support you 100 per- ington University in St. Louis. As cent,” she says. head of the medical genomics group, Ding works to uncover the genomic Looking ahead changes that lead up to and are associated with human cancer. In par- Ding says that next-generation ticular, she is part of both the Tumor sequencing technology will be a Sequencing Project and the Cancer boon for determining how cancer Genome Atlas efforts. “My research arises. These new methods will allow mostly focuses on identifying the researchers like Ding to screen more genomic alteration associated with genes, more samples, and more types human cancer,” Ding says. of cancer. “It will allow us [to see] The TSP is a multicenter collabora- the whole transcriptome, the entire tion that has a goal of mapping the exons of all genes, and the whole genomic changes that occur in lung TITLE: Research Instructor, genome. It will allow us to look at adenocarcinoma, the most common Washington University a large number of tumors for each form of lung cancer. The average five- EDUCATION: PhD, University of Utah, tumor type,” she says. “Eventually year survival rate for patients with 1998 [it] will allow us to look at every type this form of cancer is 15 percent. RECOMMENDED BY: Rick Wilson of major cancers found in humans “The low survival rate is largely due and, hopefully, with next-generation to late-stage detection, so that’s why sequencing, we can also look into we are interested in studies of this the gene called the PIK3R1 because metastasis.” cancer type because of its high over- this is the first time that PIK3R1 is all incidence, in the US and world- identified as a major cancer gene Publications of note wide,” Ding says. in GBM,” she says. Furthermore, The Cancer Genome Atlas proj- she adds, the gene mutations they Besides Ding’s work with the ect is studying a variety of can- detected were clustered together in Cancer Genome Atlas project, she cer types: glioblastoma multiforme, a coding domain that is responsible has also published a number of ovarian cancer, and squamous cell for interacting with the catalytic papers dealing with her work on lung cancer. Some of the findings domain. lung adenocarcinomas. In a Cancer from the glioblastoma arm of the Along the way, Ding has been Research paper that came out this project were published online in the encouraged by her bosses, Rick Wil- past July, Ding and her colleagues September 4th edition of Nature. In son and Elaine Mardis, to follow identified a novel MEK1 mutation in that study, Ding and her colleagues what interests her. “[Wilson] would the EGFR signaling pathway of lung found three genes — NF1, ERBB2, always say, ‘Go for it! If you think it’s adenocarcinomas. and PIK3R1 — that are significantly interesting, you should dig deeper.’ mutated in these tumors that had He has always been very supportive,” And the Nobel goes to … not previously been associated with Ding says. For example, as part of the the disease. “We’re extremely excited GBM study, Ding saw an interesting Ding’s end goal is to improve patient about this finding of mutations in feature of the PIK3R1 mutation; Wil- care. “If we can develop something that can help treatment of cancer, “This is the first time that PIK3R1 is identified any type of human cancer, I think that would be my dream,” she says. as a major cancer gene in GBM.” —Ciara Curtin

10 WWW.GENOME-TECHNOLOGY.COM______DECEMBER 2008/JANUARY 2009

Robert Riehn SEQUENCING

Stretching and Sequencing DNA

any approaches to TITLE: Assistant Professor, Looking ahead DNA sequencing North Carolina State University rely on fluorescent EDUCATION: PhD, University of In the next five years, Riehn says, Mtags to signal the Cambridge, 2003 the goal of sequencing a human different bases contained in a given RECOMMENDED BY: genome for $1,000 will most likely stretch of DNA. Instead of using tags, Robert Austin, Alan Guttmacher be met. However, he thinks that North Carolina State’s Robert Riehn sequencing will still be performed thinks that the electrical properties in large diagnostic laboratories. Fur- of DNA can be harnessed to deter- the electrical energy structure of the ther down the line, in about 10 mine its sequence — and he’s putting molecular orbitals inside the mol- years, he thinks that doctors’ offices his background in nanotechnology to ecule. And then, hopefully, if we may have sequencers that could pro- use to find sequence-specific electric choose correctly, the different bases vide low or medium-quality read- signals from DNA. “What I’m doing have different signatures.” outs to be used as a screening tool, is very basic: trying to show there is a The challenges, he adds, are get- say for a microbial or viral infection. signal and trying to show that we can ting that sequence-dependent signal “We wouldn’t necessarily be seeing make this signal sequence-specific,” and knowing how fast the strands of the resequencing everything to true Riehn says. DNA are flowing through the nano- fidelity, but simply a screening for a In his microfluidic device, Riehn channels. Though all the bases are large number of common questions,” uses nanofluidic channels with cross- different, they are still fairly similar, Riehn says. sections smaller than 50 nanometers hanging off the same sugar phos- and a few hundred microns long. phate backbones; Riehn says that Publications of note Strands of DNA are then stretched only about a third of the base ac- out in these channels and placed counts for the difference. Then, you In a PNAS paper from 2005 called between two electrodes. “The DNA have to know how fast the DNA “Restriction mapping in nanofluidic is directly between two opposing moves through the channel because devices,” Riehn and his coauthors electrodes, and the two opposing if you don’t know that, “you still restriction-mapped DNA stretched in electrodes try to attract the DNA,” don’t know what the sequence is,” their nanochannel. Riehn says that Riehn says. His team members are he says. restriction mapping is one of the currently working on measuring Riehn’s interest in this area was more basic tools in the field, but the how current flows sideways through piqued by working in Robert Austin’s effort showed “that we can really do DNA. They hope that if they choose lab at Princeton University. Riehn biology on our microfluidic devices, the conditions properly, they will says that Austin’s rigorous way of that they are not just applicable to a be able to detect a sequence-depen- asking questions has shaped how very narrow range of applications, dent signal. “Chemically, the bases he does his own research. “His ap- that we can do real biology on the have different chemical structure,” proach definitely is not one of incre- stretch-out DNA inside the nano- Riehn says. “What we hope is that mental research. He has more of an channels.” by choosing the conditions of the approach of trying to do something electrical field correctly, or of the big — try to do something big and And the Nobel goes to … energies of the electrons correctly, you may fail and you may not fail,” that we can gain some insight into Riehn says. “I like that.” “A very large-scale issue would be the eradication of transmittable dis- “What I’m doing is very basic: trying to show eases,” Riehn says. “That would be one thing that I would do if I could, there is a signal and trying to show that we can really — diagnose every person in- make this signal sequence-specific,” Riehn says stantly for exactly which pathogen they are carrying.” of his microfluidic device. — Ciara Curtin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 11

Tim Lu SYNTHETIC BIOLOGY

Letting the Bedside Inform the Bench

im Lu is in the relatively knock out networks of bacteria re- rare position of having sponsible for the resistance mutation first-hand experience at in combination with prescribing cur- Tthe bedside and bring- rently available antibiotics, he and ing his own research efforts to bear Collins have demonstrated that it is on real-life problems in the clinic. As possible to reduce the mutation rate a researcher also pursuing his MD, 1,000-fold and kill bacteria 30,000 Lu uses synthetic biology to combat times more effectively than with just bacterial infections, with a specific the antibiotic alone. focus on engineered bacteriophages. The initial inspiration for this came Looking ahead to him while fulfilling his med school duties: examining dialysis patients The long-term vision for the bac- with indwelling catheters, many of teriophage that can eliminate anti- whom suffer from severe bacterial biotic-resistant bacteria is to use it infections caused by biofilms. “There first against the most serious types are a lot of biofilms in all sorts of of infections such as MRSA, which medical devices, such as indwelling TITLE: Research Assistant, MIT can’t easily be eradicated. At pres- catheters. You can get a bacteria that EDUCATION: PhD, Harvard-MIT ent, Lu and Collins are using mouse sticks to the catheter surfaces that Division of Health Sciences and trials and hope to eventually work are really hard to eradicate with any Technology, 2008; currently pursuing with the Centers for Disease Control conventional antibiotics,” Lu says. MD at Harvard Medical School and Prevention to start gaining more “So you have to rip out the catheter RECOMMENDED BY: James Collins clinical acceptance. In the future, and insert a new one, which causes Lu says, they would like to engineer morbidity in a lot of patients.” their bacteriophage to work around a Instead of inventing a nuclear- been aware of their potential for some particular resistance to offer a more powered can of Lysol, Lu saw an op- time. “The biggest hurdle for us going rational approach to fighting bugs portunity to use his synthetic biology forward is acceptance of the medical that are constantly evolving. skills to engineer a bacteriophage community and the FDA. We’re us- capable of destroying the biofilm by ing engineered bacteriophage, which Publications of note penetrating the extracellular wall and are virus, even though they only attacking the bacteria inside. Last affect bacteria,” he says. “People are In a 2007 paper published in PNAS year, Lu and Boston University’s Jim becoming increasingly interested in entitled “Dispersing biofilms with en- Collins demonstrated that this was using bacteriophage, so I don’t think gineered enzymatic bacteriophage,” Lu possible using an engineered E. coli- this is going to be a problem in the and Collins showed that engineered specific phage expressing dispersin next 10 or 20 years — but there’s biofilm-destroying bacteriophage were B, an enzyme capable of break- obviously a lot of work that needs several orders of magnitude better ing down several different types of to be done to prove to [the] medical than wild-type bacteriophage at biofilms. According to their initial community that this is something eliminating biofilms. experiments using E. coli biofilms that’s viable.” on a plastic surface, the engineered In addition to fighting biofilms, And the Nobel goes to … bacteriophage was capable of killing engineered bacteriophages can also 99.997 percent of the biofilm cells. be used to fight antibiotic-resistant Lu says he would like to receive But the US Food and Drug bacteria, another issue with which the Nobel for creating a long-term, Administration has not yet approved Lu is familiar from his experience sustainable solution to treating anti- bacteriophages for use in humans, as a physician-in-training. Lu says biotic-resistant bacteria. although the medical community has that by inserting bacteriophages that — Matthew Dublin

12 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

______

Thanks For Your Support Genome Technology extends its sincere thanks to the advertisers in this issue, whose sponsorship helped proved a travel stipend honorarium for each of Tomorrow’s PIs

David Mathews STRUCTURAL BIOLOGY

Looking for Secondary Structure

he most widely known protein-coding genes. We may have secondary structure of many more noncoding RNAs that RNA is the cloverleaf- are functioning at the level of RNA, T shaped configuration of so there’s a lot of interest to be able transfer RNA. The three loops of the to find these genome sequences,” he cloverleaf have specific roles during says. Mathews’ group has also de- translation at the ribosome. There veloped an algorithm that searches are, however, other RNA arrange- genomes for noncoding RNAs. ments that occur, and their functions Another area that RNA secondary are not always as clear. The Univer- structure knowledge will help is in sity of Rochester’s David Mathews is designing effective siRNAs, Mathews building algorithms to predict sec- says. Providing complementary short ondary structures of RNA and apply- duplex RNAs may silence a message, ing that knowledge to finding novel, but it isn’t always effective. “We’ve noncoding RNA in the genome and looked at that as a problem of equi- uncovering what those RNAs do. librium binding and so approaching In addition, he says that knowing it that way we have an algorithm more about secondary RNA structure TITLE: Assistant Professor, that can design effective siRNAs for might help researchers design better University of Rochester a given mRNA target,” he says. and more effective siRNAs. “We’re EDUCATION: PhD, University of best known for our work in predict- Rochester, 2002; MD, University Looking ahead ing secondary structure,” Mathews of Rochester, 2003 says of his lab. RECOMMENDED BY: Mathews says the goals for the next Mathews’ group wants to be able to Alan Guttmacher, Doug Turner five years are to find all the noncod- predict, from any given sequence, if ing RNAs and to move toward better there will be an RNA structure and, prediction of three-dimensional RNA if so, what base pairs will form. As a ture ranges. With a single sequence, structures. “If we are able to find bioinformatics and computational bi- he says, the predictions are about more in noncoding RNAs, then we ology group, the team has developed 70 percent accurate; with multiple have more information to use to de- an algorithm to detect the RNA struc- sequences, that figure can reach 90 termine three-dimensional structures ture common to two homologous percent. He says people working on — and if we’re better at predicting sequences. “We’d like to be able to, this problem use different approaches, three-dimensional structures, we’re given a set of homologous sequences, which has resulted in variation going to be able to more effectively be able to determine the secondary in accuracy. “But I’d say none is find noncoding RNAs with better structure of those sequences with perfect,” he says. sensitivity and specificity,” he says. 100 percent accuracy. That would Studying RNA structure leads improve our ability to determine to questions plaguing genomics, Publications of note three-dimensional structures and it Mathews says —in particular to the would improve our ability to find attention paid to noncoding RNAs. In 2006, Mathews and his team noncoding RNAs,” Mathews says. “They may, for example, explain why published a paper in BMC Bioinfor- Currently, the accuracy with which higher organisms are more compli- matics. “That’s where we apply our Mathews and others working in the cated than lower ones even though algorithm for finding common sec- area of predicting secondary struc- we don’t have dramatically more ondary structures and use that to find regions in genome alignments “We may have many more noncoding RNAs that are likely to contain structured RNA,” Mathews says. that are functioning at the level of RNA.” — Ciara Curtin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 15

Bojan Zagrovic STRUCTURAL BIOLOGY

Finding Order in Disorder

s a grad student who binding sites. “If you tap into these helped Stanford’s Vijay allosteric effects, could you actually Pande develop the Fold- affect the function of an enzyme by Aing@Home project, Bo- creating something that would bind jan Zagrovic knows what the current somewhere else,” he says, “not neces- protein modeling tools can and can- sarily in the active site, but still have not do. And while a lot of progress effect in the active site?” has been made in the field of computational proteomics, there’s still Publications of note much to be figured out. As group leader of the computa- In 2005, Zagrovic published a paper tional biophysics lab at the Mediter- in PNAS that explored the conforma- ranean Institute for Life Sciences in tion of unfolded polypeptides. In the Split, Croatia, Zagrovic uses molecu- study, he combined wet lab work and lar simulations to model the folding molecular modeling using the Fold- and binding dynamics of mainly ing@Home cluster and found that protein-protein interactions, but also the structure of unfolded proteins lipids and DNA. “It’s 99 percent theo- TITLE: Group Leader in Computational does reside in the previously de- retical,” Zagrovic says. After leav- Biophysics, Mediterranean Institute scribed configuration, a polyproline ing Stanford in 2004, Zagrovic has for Life Sciences type II helix, “but that it is much, continued to use and develop the EDUCATION: PhD, Stanford much more compact than previously Folding@Home distributed comput- University, 2004 thought,” Zagrovic says. “In other ing cluster centered at Pande’s lab in RECOMMENDED BY: Vijay Pande words, what we have shown is that order to look at “how dynamics and locally the chain is PPII, but when structure are connected, and related it comes to its long-range structure to function.” [and] more sampling.” As it stands, it is still a compact random coil.” It One of his lab’s main areas of in- processors are capable of render- was one of the largest simulations terest outside protein folding is the ing only a small fraction of what he to date — the team employed seven unstructured nature of proteins. needs to see in order to understand different commonly used models, or Natively unfolded proteins, or “in- many biological processes. “There’s force fields, to simulate the polypep- trinsically unstructured proteins,” two [or] three orders of magnitude tide configurations. he says, are common and present a — if not more — difference between new frontier for computational sim- what we want [to see] and what we And the Nobel goes to … ulation. “It turns out that almost 30 can,” he says. percent of eukaryotic proteins actu- If Zagrovic were to win the Nobel ally have significant regions [where] Looking ahead prize, he would hope to get it “for there’s simply no structure. They do proving that proteins and biomol- not conform to the 3D structure- Zagrovic will continue studying ecules, in general, are more much equals-function paradigm,” he says. what he thinks could become a new flexible than we think,” he says. “The “The problem is the standard tech- paradigm for understanding unfold- way we picture things right now is niques of structural biology are not ed protein structure. In the next five quite ordered still; our logic is still capable of describing these mol- years, he hopes to apply computa- very much mechanistic. But I have ecules.” tional modeling to solving problems this feeling that things are much The limiting factor in his work, of associated with the “entropic com- more fuzzy, things are much more course, is computational power, and ponent to protein activation,” which fluctuant, things are much more in the coming years he hopes to have could have a clinical impact when it crazy than we think.” “better algorithms, faster computers, comes to finding ideal drug target — Jeanene Swanson

16 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

Oliver Rando STRUCTURAL BIOLOGY

Opening the ‘Black Box’ of Chromatin

fter years of studying ture, Rando says. “Characterization transcription in other of beads on a string is, at this point, people’s labs, Oliver mature. We can find nucleosomes. ARando, now at the Uni- The folding of beads on a string — versity of Massachusetts Medical the next level of compaction — is School, is finally leading a lab of his called 30-nanometer fiber, and at own focusing on the genome-wide this point, no one has any hint for structure and function of a key regu- how to think about mapping at 30- lator, chromatin. nanometer fiber. But I think it will Rando studies everything from the be tremendously illuminating to do sequence of repeating histones to so,” he says. nucleosome positioning, covalent In the immediate future, Rando modifications, and the histone vari- thinks the community will move ants themselves. “We’re interested toward mapping chromatin states. in how DNA is packaged in the cell “How do nucleosomes move when — in other words, what chromatin you turn on a gene, or, in our case, structure looks like,” he says. “We’re during genomic replication?” interested in that both independently TITLE: Assistant Professor, as well as a potential carrier for Department of Biochemistry and Publications of note epigenetic information.” He runs a Molecular Pharmacology, University of broad array of tools, spanning home- Massachusetts Medical School A lingering question in Rando’s made and commercial microarrays to EDUCATION: MD/PhD, mind is why there are so many his- deep sequencing, to make sense of Stanford University, 2002 tone modifications. In a paper pub- this information. RECOMMENDED BY: Phillip Zamore lished in PLoS Biology in 2005, he Over the past several years, Rando and his team used a high-resolution has focused on mapping chroma- tiling array to look at the occur- tin structure in yeast, and how that early years of training that chromatin rence of combinations of 12 histone changes as a cell proceeds through its was a fairly mysterious black box modifications across thousands of cycle. “All of these basic mechanistic and often people in the transcription nucleosomes in growing S. cerevisiae. questions about how nucleosomes field would invoke chromatin when They found that two groups of co- move and interact with each other they didn’t understand something,” occurring modifications could dis- after replication have huge conse- he says. While at Jerry Crabtree’s tinguish nucleosomes at one location quences for how and whether you Stanford lab, Rando did his PhD on from another. Rando expects this to can inherit chromatin states,” he the chromatin remodeling complex, become more of a focus in the com- says. He notes that while a majority which converts the energy released ing years. of people believe chromatin states to during ATP hydrolysis to remodel be heritable, he contends that there’s nucleosome structure. “We realized And the Nobel goes to … no hard proof yet. “Whether chroma- that there was no way to find lots of tin states are heritable is, to my mind, nucleosomes at once, and that’s what Asked what he’d like to win the still an open question.” led me to start working on how to do Nobel for, Rando says his eye isn’t Since his undergrad days, Rando these mapping things on a genomic on the prize. “I distrust people whose has always worked in transcription scale.” goal in science is to win prizes.” labs, and it was from these early When pressed, he says, “I suppose experiences that he noticed how Looking ahead it would be for discovering an epi- little people knew about what was genetic therapy that cured a huge regulating the process of transcrip- A big technical challenge is describ- number of cancers.” tion. “It became very clear over my ing the next level of chromatin struc- — Jeanene Swanson

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 17

______

Julius Brennecke RNA INTERFERENCE

Parsing Nature’s Elegant Solutions

ulius Brennecke had big Looking ahead plans to pursue a career in medical research, but As Brennecke makes his way to Jstints as a field assistant Vienna to set up his own lab at in the Galapagos Islands and in the IMBA, where he will be a group Serengeti convinced him to change leader starting in January, he says course. “The adventures that I had Drosophila will continue to be his [there] just reinforced my attachment model org of choice thanks to the to nature and to [understanding] high level of conservation between living processes,” he says. “I realized flies and mammals in the key path- that what I’d like to do most was to way of interest. combine that passion and interest with molecular biology to basically Publications of note come to an understanding of how processes function on the molecu- In April 2003, Cell published a pa- lar level.” What has always amazed per that largely sums up Brennecke’s him most about biological processes, PhD work. “Bantam encodes a de- Brennecke says, is that when he con- TITLE: Postdoctoral Fellow, Cold velopmentally regulated microRNA siders how he might have solved Spring Harbor Laboratory, through that controls cell proliferation and a particular problem, the way that 2008; Group Leader, Institute of regulates the proapoptotic gene hid nature actually solved it is “always Molecular Biotechnology in Vienna, in Drosophila” describes the work so much more elegant and so much starting January 2009 that went into proving that a par- more functional.” EDUCATION: PhD, EMBL Heidelberg ticular mutation in the fly genome He was working on his PhD at and Ruprecht-Karls University was actually a member of the newly EMBL in Heidelberg when serendip- Heidelberg, 2004 discovered class of miRNAs. ity struck. Brennecke was tasked RECOMMENDED BY: Victor Ambros Another Cell paper, this one pub- with making sense of a Drosophila lished in 2007 and entitled “Discrete mutation that had proven unwilling small RNA-generating loci as master to give up its secret. He happened piRNAs serve as “a sort of immune regulators of transposon activity in to be on journal club duty when system on the RNA level,” he says — Drosophila,” provides a glimpse of the first papers came out describing they appear to silence transposons, his postdoc years in Hannon’s lab, microRNAs — Brennecke followed preventing them from hijacking the Brennecke says. During this time, the inspiration and, sure enough, genome. It’s a system he plans to he investigated piRNAs, which are the mutation turned out to be a study in more detail. heavily involved in a genome’s ability member of this class of small RNAs. At this point, he and Hannon’s team to protect itself from transposons. “We went on to explore the microRNA have a “bird’s eye view” of piRNAs targeting [mechanism],” he says; the based on “unique patterns which are And the Nobel goes to … team merged computational and highly suggestive of how the system experimental data to demonstrate can work,” he says. More data must Brennecke says he was once told how the miRNA pairing process be gathered, but what is completely that most Nobel laureates win for a worked. clear so far is the importance of the discovery they made before the age Brennecke is just wrapping up a piRNA pathway: when it’s deleted of 25 — and, based on that, he just postdoc with Greg Hannon at Cold in model organisms, it results in doesn’t think he has a chance. “I have Spring Harbor Laboratory, in which full sterility, Brennecke says. “The a strong feeling this is well over [for he took advantage of deep sequenc- protection against [transposons] is me],” he says. “I don’t see anything I ing technologies to study piwi-inter- of vital importance for the species to did so far as real pioneer work.” acting RNAs. The team found that keep existing.” — Meredith Salisbury

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 19

Kevin Morris RNA INTERFERENCE

Another Mode of Gene Silencing

aking an important search on genetic-based therapy, and discovery while still during the course of his studies, his considered young is curiosity about RNAi got the better of Mgreat, but not nec- him. He designed a project separate essarily in a funding climate that from what he was working on be- isn’t laying grant money at your feet cause he thought it’d be “interesting for follow-up studies. This situation to see if we can just target a promoter could describe that of Kevin Morris, and turn it off.” Subsequent post- who was first author on a paper de- graduate studies with John Rossi al- scribing transcriptional gene silenc- lowed him even more time to figure ing for the first time in 2004, while out how TGS was working. he was still a postdoc in David Loo- ney’s lab at UCSD. Today, Morris is Looking ahead an associate professor at Scripps and his work is focused around elucidat- Morris would like to see better ing the function of that mechanism. ways to knock down genes in hu- Transcriptional gene silencing, man cells. Right now, he relies on a or TGS, differs from the more well TITLE: Assistant Professor, combination of biotin-labeled oligos known post-transcriptional gene Department of Molecular and or siRNAs, pulldowns, chip assays, silencing in that noncoding RNAs Experimental Medicine, and “tweak[ing] protocols that are turn off transcription by interacting The Scripps Research Institute out there to fit to what we need.” If with a gene’s promoter. In his study, EDUCATION: PhD, University of he could invent a technology, it’d be Morris introduced siRNA into the California, Davis, 2001 a “promoter array that could measure nucleus of cultured human cells and RECOMMENDED BY: John Rossi directionality of transcription.” This, found that silencing worked through he says, would allow him to distin- an “epigenetic mode” where the guish the role of bidirectional tran- nucleosome was altered structurally, two graduate students, continues to scription in gene regulation, cancer preventing RNA polymerase from work on studying TGS. He wants to development, and HIV infection. binding and transcription from be- know exactly how endogenous non- Separate from transcription factors ginning. Instead of having transient coding RNA can induce the effect and miRNAs, noncoding RNAs have silencing, though, TGS can affect and how it can be therapeutically just begun to make their mark in the cells for a longer time — a month targeted to genes involved in HIV area of gene regulation, and Morris instead of three or four days, which and cancer. He’s also partnered with hopes that in five years people will is common to post-transcriptional Roche to study how noncoding RNAs be paying more attention to them in silencing — opening up the possibil- are involved in stem cell differentia- this context. “There’s a lot more RNA ity for more effective therapeutic gene tion, and whether or not TGS can be modes of regulation that we’re just knockdown. used to revert cells to a pluripotent now starting to see, and it’s really go- “What happens is you get this sort state. “The technology doesn’t exist ing to be fascinating, in my opinion, of remodeling that occurs at the gene right now for looking at noncoding in the near future,” he says. promoter,” Morris says. “If you were RNAs in this sense,” he says, not- considering water and snow and ing that high-throughput sequencing And the Nobel goes to … rainfall, [TGS is] stopping the rain could work. Roche is working on from actually falling, whereas post- generating an array-based platform As for the Nobel prize, Morris says transcriptional silencing is stopping to study this. he “would probably go the route of the water from reaching the ocean by Going into his PhD, Morris wanted Jean Paul Sartre and decline to take building a dam.” to work on HIV. As a postdoc at UCSD, that.” At Scripps, Morris, along with his he worked at the Center for AIDS Re- — Jeanene Swanson

20 WWW.GENOME-TECHNOLOGY.COM______DECEMBER 2008/JANUARY 2009

Greg Cooper STRUCTURAL VARIATION

A Compelling Look at Variation

hen Greg Cooper number variants are a great example applied to two post- of this.” But tracking down the rare doc positions at the variants will be particularly chal- WUniversity of Wash- lenging, requiring not only signifi- ington — one with Evan Eichler, the cant drops in the cost of sequencing other with Debbie Nickerson — what but also access to samples from enor- he really wanted was to move from mous populations. “It’s going to come mammalian genomics research to down to sequencing and picking up work that had more direct applica- all those rare SNPs,” he says. tion in understanding human genet- A key to coming up with the “com- ics and population characterization. pelling biology” explanations will Accepted by both PIs, Cooper is now be improved functional annotation, doing a joint postdoc project that has Cooper says. Back in his grad school put him right in the thick of the very days at Stanford University School of research he found so appealing. Medicine where he earned his genet- The project, which began in 2006, ics PhD with advisor Arend Sidow, aims to connect structural variation Cooper was involved in the ENCODE data from the human genome to TITLE: Senior Research Fellow, project that has placed a premium on the common traits linked to them. University of Washington this kind of work. He began by studying the genetic EDUCATION: PhD, Stanford effects of statin response, but the University School of Medicine, 2006 Publications of note rapid progress in technology for in- RECOMMENDED BY: terrogating structural variation, as Evan Eichler, Debbie Nickerson To get more of a sense of his work, well as scientists’ understanding Cooper says it’s a good idea to of the mechanisms involved in it, check out “Systematic assessment of prompted him to expand his scope. predictive tool, that’s almost use- copy-number variant detection via Studying variation in the HapMap less. That’s not clinically relevant genome-wide SNP genotyping,” a samples has, for example, become to tell somebody” about a variant paper he co-authored that was pub- a major focus of Cooper’s lab work, of negligible effect, he adds. “The lished in Nature Genetics. The paper he says. only way to make good on that is builds on previous work from the A key goal is to find the real links to learn about the biology,” he says. Eichler lab analyzing genomic data between this kind of variation and its His goal is “coming up with ways to for nine individuals that was pub- phenotypic effect. While much of the provide a mechanistic understanding lished earlier this year. community has gotten tremendously to explain the associations that we’re excited about genome-wide associa- observing.” And the Nobel goes to … tion studies, Cooper notes that the One possible reason that would problem so far is that most of the re- explain why so many genetic variants Not me, Cooper says. “I see genom- sults have provided “minimal infor- don’t appear to have a major effect is ics as becoming such a collaborative mation” about variations of “modest the possibility that much of the phe- enterprise,” he says, “it seems like effect.” That isn’t going to radically notypic variation is actually caused the notion of a Nobel prize being change patient care, he says. “As a by rare variants, Cooper says. “Copy awarded to a single person for a discovery” is a paradigm that won’t work much longer for the field. “I Finding variations of modest effect won’t wish I had an answer that I was on radically change patient care. “As a predictive the verge of something extraordinary,” he laughs. tool, that’s almost useless,” Cooper says. — Meredith Salisbury

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 21

______

Adriana Briscoe GENE EXPRESSION

It’s All in the Eyes

driana Briscoe has spent Looking ahead the past 10 years looking into eyes — of but- Briscoe hopes to see the field ad- Aterflies, that is. Briscoe vance not just technically, but in looks at the genes encoding visual terms of increased collaborations. pigments in the photoreceptor cells “I would like to see more work in of butterfly eyes and has shown that our field integrating population ge- much of the diversity of butterfly netics, molecular evolution, protein wing color can, in fact, be attributed biochemistry, neurophysiology, com- to variability in what colors these putational modeling, and behavior pigments are sensitive to. linking the visual worlds of animals “My lab is studying the evolution to their predators, and in particular, and functional genomics of butterfly linking biologically relevant signals color vision,” she says. “We’re trying to observers,” she says. to understand how butterflies see the world, and what forces, natural Publications of note or sexual selection, have shaped the evolution of their eyes.” To that end, TITLE: Associate Professor, In a paper published in the Journal she employs a range of tools, from Department of Ecology and of Experimental Biology in 2006, Bris- DNA sequencing to gene expression Evolutionary Biology, coe and colleagues found that males profiling using in situ hybridization to University of California, Irvine and females of one species of butter- phylogenetic computational analysis. EDUCATION: PhD, Harvard University, fly have two distinct sets of receptors. Briscoe uses transgenic Drosophila to 1999 “[They] literally have different eyes, express butterfly visual pigments in RECOMMENDED BY: Marcie McClure [and] these eyes are unique com- photoreceptor cells. pared to other butterflies,” she says. As a grad student at Harvard, They found that in the lycaenid but- Briscoe says, “I had this intuition ously thought to be a one gene-one terfly, a species with sexually dimor- that the eyes of butterflies might receptor pattern of expression. Since phic wings, males have a dorsal eye be as diverse, evolutionarily, as the then, she’s looked at butterflies from with only UV- and blue-sensitive pig- color of their wings. But at the time, all of the five major families, “and ments, while dorsal eyes of females no one knew anything about the they all have different visual sys- have an additional third pigment that molecular basis of vision.” So Bris- tems based on the photoreceptors is sensitive to long wavelengths and coe went on a mission to find out, that are present in their eyes,” she is co-expressed with blue-sensitive publishing one of the first papers says. “They literally see the world pigments. This increased visual ca- on the cloning of a visual pigment through different eyes.” pacity has likely driven the diversity in the swallowtail butterfly. “I dis- Because her current approach is of butterfly wing coloration, Briscoe covered that this particular species to integrate many levels of biologi- believes. of butterfly had more rhodopsin cal analysis, she says, her biggest genes than were expected based on challenge is in the area of protein And the Nobel goes to … the physiological studies that had biochemistry. “We have moved into been published,” she says. the area of protein biochemistry, and As for the Nobel, Briscoe would During her postdoc, she began to my proteins of interest, invertebrate veer off and hope to win it for spatially map the expression pat- rhodopsin-based photoreceptors, are “a totally unrelated topic, curing terns of these duplicate genes, some notoriously tricky to express and schizophrenia, something that actu- of which were co-expressed in dif- functionally characterize,” she says. ally would really help people.” she ferent receptor cells, overturning “That’s what I spend most of my time says. the idea of what had been previ- agonizing over.” — Jeanene Swanson

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 23

Uwe Ohler GENE EXPRESSION

Imaging Gene Regulation

s a computer scientist images,” Ohler and colleagues im- with a biology back- aged the expression pattern of one ground, Uwe Ohler gene, tagged with a green fluorescent A knows a thing or two marker, in many different tissues, about collaboration. On his web- and then mapped that data back to site at Duke University’s Institute for an atlas image in order to get relative Genome Sciences and Policy, where expression values. “We have been he’s an assistant professor in bio- working on a robotic platform to statistics and bioinformatics, he’s scale up the generation of images,” listed several current collaborators. he says, “and a good property is that They range from colleagues at the we can do that in living plants and IGSP to researchers at the University thus get expression over time from a of Chicago and the Max Planck In- single specimen.” stitute. For the kind of work he does — computationally predicting and Looking ahead mapping gene regulatory elements — it’s essential to involve a multi- Ohler sees more and more people disciplinary cast. TITLE: Assistant Professor, taking advantage of high-throughput Ohler’s lab focuses on transcrip- Biostatistics & Bioinformatics, microscopic image data to decipher tion start site and microRNA target Duke University gene networks, particularly in the site prediction. While his lab aims to EDUCATION: PhD, University of areas of gene regulation, gene ex- map regulatory sequences, the team Erlangen-Nuremberg, 2002 pression, and regulatory genomics. is also putting these predictions to RECOMMENDED BY: Hunt Willard He expects that, in time, image data functional test using high-through- will be “more high throughput and put microscopy. To study gene ex- available.” pression in plant roots, incorporating a change in the expression of the Ohler also sees next-generation se- imaging allows Ohler to “look at genes,” he says. quencing tools as having a big impact individual expression profiles from a Ohler started his career majoring on his work. In contrast to micros- single gene or a few genes, and look in computer science and minoring copy, “the technology’s not going to at that in a living organism under the in biology at University of Erlangen- be the limiting part,” he says. “It will microscope — and actually be able to Nuremberg in Germany. It was while be more a matter of keeping up with tell exactly where and when was the working on his honors thesis that the pace of the technology develop- gene expressed and how that could he began looking at promoter se- ment as a computational person and change under different conditions,” quences. That “got me hooked on adjusting our models to actually deal he says. “Microarrays only tell us the this whole area of computational with that data in terms of just basic average story.” biology,” he says. During his PhD at infrastructure.” Recently, Ohler won a Human the University of Erlangen, he spent Frontier Science Program. In this three years as a visiting researcher for And the Nobel goes to … work, Ohler looks at individual ex- the Berkeley Drosophila Genome Proj- pression patterns of a handful of ect on a grant from the Boehringer If he were to win the Nobel, Ohler genes in Drosophila embryos under Ingelheim Foundation. suggests petitioning the Nobel com- the microscope, and then compares mittee to add another category to those to patterns in different species Publications of note include computational research. “I and back to the regulatory DNA se- think it would be pretty astonishing quences. “Ultimately what we hope In a 2006 Bioinformatics paper enti- in general if somebody wins for work to do is see where the sequences tled “Quantification of transcription that is mostly theoretical.” change and how that correlates with factor expression from Arabidopsis — Jeanene Swanson

24 ______WWW.GENOMETECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

Marian Walhout GENE EXPRESSION

A Fresh Look at Differential Expression

ometimes taking a back- C. elegans. “We are further automat- ward approach to a coming our pipeline and we are almost mon problem can yield there, so in three years or so we Ssurprising results. Such is should have much more comprehen- the thought process of Marian Wal- sive networks that we can study and hout, who is using a roundabout way get the idea of the principle for how of studying differential gene expres- they control gene regulation within sion in C. elegans. the worm,” she says. The standard operating procedure And if she can get the funding, for this kind of gene expression Walhout says she would also like to research is usually a method centered apply the approach she has devel- on transcription factors, wherein one oped to humans. “Because now we starts with a transcription factor of have set up all the technology in the interest and then proceeds to locate worm, now we are ready to go to an where it binds in the genome. Wal- even more complex problem, which hout is going the other way around is the human genome,” she says. “So by taking a piece of DNA and then that is midterm, but even longer attempting to find out the factors that TITLE: Associate Professor, University term, it will be very exciting to start bind to that piece of DNA. of Massachusetts Medical School comparing those networks.” “Technically this approach is differ- EDUCATION: PhD, Medicine Utrecht ent because we use a method called University, The Netherlands, 1997 Publications of note the yeast one-hybrid system, whereas RECOMMENDER: Marc Vidal the method that has been used a lot In 2006, Walhout and her colleagues is the yeast two-hybrid system, so published “A gene-centered C. elegans it is different from what anybody he was interested in understanding protein-DNA interaction network” in else is doing in the field,” she says. the human genome from the view Cell. The team demonstrated for the “I’m not saying one-hybrid is better of protein-protein interactions, and first time its approach to differential or is more important, but that it’s that I liked, even though it was a gene expression, which was in oppo- complementary — and this is what little enigmatic to me at the time,” sition to what the field had been doing we need, different methods that can she says. “Then we met and really hit up to that point. The authors postu- tackle the problem in different ways it off. We are completely like-minded lated that highly connected transcrip- and from different angles. And that’s in science, and both of us benefited tion factors were more important for our unique approach to the problem tremendously from working with the survival of the nematode when that no one is doing.” each other, so it was highly syner- compared to transcription factors After finishing what she calls a gistic, which was just fantastic.” with fewer connections, suggesting “hard core” PhD in the biochem- that there is a multi-layered system of istry of transcription in her native Looking ahead gene regulation. Holland, Walhout was eager to find the best place to do a postdoc in Walhout says that ultimately her And the Nobel goes to ... the US; Marc Vidal, who has a lab lab has two big genome-related goals at the Dana-Farber Cancer Institute, for the long term. The first is to go “I think our work is a very impor- came highly recommended. “Marc one or two orders of scale more than tant contribution to the field,” she works in yeast, and that I liked, and what they are currently able to do in says. “And that is something I would like to be recognized for by the com- “This is what we need, different methods that munity, even though it may not be Nobel accomplishment.” can tackle the problem in different ways.” — Matthew Dublin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 25

______

Paul Flicek BIOINFORMATICS

In the Informatics Trenches

s the head of the Verte- the number of base pairs that a big brate Genomics Group genome center can sequence today at the European Bioin- with next-gen technologies,” Flicek Aformatics Institute and says. “It used to be that the whole a co-leader of the data flow group Human Genome Project could be for the 1,000 Genomes Project, Paul done in a week, and now it’s just a Flicek is intimately familiar with the few hours. Keeping up with that and ongoing battle to make sense out making sense of it is a big challenge of the endless stream of next-gen because our ability to produce data sequencing data. Flicek helps is way ahead of our ability to analyze guide the vertebrate genomics group and make sense of it.” in its responsibilities for providing the comparative, variation, and func- Looking ahead tional genomics resources within En- sembl, a joint project led by EBI and Flicek says that improvements in the Sanger Institute to maintain eu- sequencing accuracy will be critical karyotic genome data. And in his TITLE: Team Leader, European to accelerating how scientists can work for the 1,000 Genomes Proj- Bioinformatics Institute apply that data. “A massive change ect, which already has upwards of EDUCATION: PhD, in the accuracy of sequencing would 3 terabases of data, he has the daunting Washington University, 2004 mean that the amount of sequenc- task of getting the data processed so RECOMMENDED BY: ing that we generate in a project like that it can be used and analyzed by the Alan Guttmacher the 1,000 Genomes Project or in community. the ENCODE project, we could do Before he took up informatics arms many different things very quickly,” on the front lines of next-gen data finishing his PhD, Flicek went to join he says. That’ll be a big step, though: management for large-scale genome EBI for his postdoctoral work, where Flicek’s wish would be to get raw projects, Flicek was a graduate stu- he continued his genome annotation data quality “a million times more dent who had his sights set on study- efforts and also became a member of accurate” than it is today, “so that the ing tissue engineering and artificial the ENCODE project. chance of an error in the sequencing organ production. An introductory EBI is also where Flicek met Ewan was than one in 3 billion.” course at Washington University on Birney, who gave him a practical computational molecular biology led perspective on how to approach real- Publications of note by Sean Eddy changed all that. “I was world bioinformatics problems, he in that course for about three weeks says. “One of the aspects of working In 2007, Flicek and a team of re- when I decided that I was going with Ewan and the way he thinks searchers at EBI and the Wellcome to do [computational biology] rather [helped] me understand the real im- Trust Sanger Institute published than anything else I had decided to portance of the pieces of the puzzle “Ensembl 2008” in Nucleic Acids do at the time,” Flicek says. “That for bioinformatics, and as a side Research. The team provided an up- was at the same time when human effect, once the large-scale pieces get date to the research community on genome sequencing was ramping up built, to be able to handle data that new additions to the project, includ- at Washington University and the most other people would struggle to ing extensive support for functional whole excitement around finishing handle,” says Flicek. genomics data in the form of a special- the human genome was very real, One of the biggest challenges he ized functional genomics database, so the first work that I did was faces is next-gen sequence data. “I genome-wide maps of protein–DNA on gene prediction and comparative have a slide that I give that compares interactions, the Ensembl regulatory genomics-based gene prediction with the number of base pairs sequenced build, and other improvements. the program TwinScan.” Soon after for the Human Genome Project to — Matthew Dublin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 27

Carl Kingsford COMPUTATIONAL BIOLOGY

A Computer Scientist Takes on Transcription

arl Kingsford has one for teaching him the value of due foot planted firmly in the diligence in research and in put- analysis of biological net- ting papers together. “She has a very Cworks and the other in high standard for something being bacterial and viral genome organi- publishable, and that’s something zation and evolution. For biological that has influenced me greatly,” he network research, Kingsford is work- says. “You don’t publish the smallest ing on addressing the problem of publishable unit. You work through obtaining protein-protein interaction all the possible bugs and different data from cells in a high-throughput ways of looking at something until method. He says the challenge is you’re really sure you understand it.” that people want to be able to ana- He also credits Steven Salzberg with lyze these large networks to figure encouraging him to keep a focus on out how they’re organized and how practical, high-impact tools that are they can be used to learn what the really useful for biologists looking to proteins are doing in the cell. To this solve specific problems. end, he is focusing on how to use One thing that would help his mathematical programming to look TITLE: Assistant Professor, studies would be technology that at these networks and predict protein Department of Computer Science, would allow for high-throughput, function. University of Maryland low-noise assays capable of identify- And on the bacterial genome analy- EDUCATION: PhD, Princeton ing two proteins and tracking when sis side, he is developing software to University, 2005 and where they interact. “That would look at bacteria and the influenza RECOMMENDED BY: Steven Salzberg make a lot of the questions we try virus. There are various projects un- to answer about the evolution and der that umbrella, one of which is a organization of biological networks freely available program he and his entist. In his graduate studies, he easier to answer,” he says, “but it colleagues developed called Trans- was mostly focused on computational would take some of the fun out it TermHP. This tool enables research- biology and protein structure predic- because it would be like giving you ers to predict particular sequences of tion that honed his algorithm and the answer.” transcription terminators in bacteria. coding skills. This is the same skill “Basically it’s a fundamental feature set he uses to address the chal- Publications of note of the organization of the bacterial lenge of extremely noisy data from genomes that divide up the genome biological network studies. “It’s a In a paper published in Genome into genes that get transcribed at the technical issue [that] we’re think- Biology (“Rapid, accurate, compu- same time. … This is a computa- ing about mostly, and it’s how we tational discovery of Rho-indepen- tional way of finding those signals,” can deal with this extremely use- dent transcription terminators il- Kingsford says. “The bacterial and ful, but also very noisy, data,” he luminates their relationship to DNA viral genome is a grab bag of a few says. “And that’s where computer uptake”), Kingsford and his col- different things, but that’s the main scientists can excel, because we’ve leagues describe TransTermHP and one that we’ve done.” developed a lot of methods for deal- its ability to detect Rho-independent Although the biological network ing with uncertainty of data sets transcription terminators. Using research is a relatively new area for over the years.” the program, the team predicted Kingsford, the genome organization Kingsford credits his PhD advisor the locations of terminators in 343 research is a direct result of his Mona Singh, a professor of com- prokaryotic genomes, representing earlier training as a computer sci- puter science at Princeton University, the largest collection of predictions available. “That’s where computer scientists can excel.” — Matthew Dublin

28 ______WWW.GENOMETECHNOLOGY.COM DECEMBER 2008/JANUARY 200

James Taylor COMPUTATIONAL BIOLOGY

Researching to Help Researchers

ames Taylor is one research- next-gen sequencing platforms and er dedicated to making life density increases in tiling arrays. easier for other research- Jers. Taylor is addressing Looking ahead what he views as a severe lack of user-friendly interfaces for genomic Considering future plans, Taylor data management and effective ways says his goal is for disparate research to make data analysis reproducible groups to communicate more effec- and easily shared. The UCSC Ge- tively through an informatics infra- nome Browser is a beautiful thing, for structure. “I think a lot of the data instance, but what is an investigator storage and the databases are pretty to do after downloading millions of ad hoc, so five years down the road SNPs and gigabytes’ worth of align- we are going to face difficulties figur- ments? ing out how things were done in the To help overwhelmed scientists get past,” he says. “What I’d really like to organized and make the most out of see is the community develop a lot of all the data, Taylor and his colleagues these communication standards and are developing Galaxy, a Web-based TITLE: Assistant Professor, really have a focus on the question of genome analysis tool set that allows Emory University both reproducibility and openness in users to conduct on-the-fly analy- EDUCATION: PhD, Pennsylvania research.” sis of multiple genome data sets in State University, 2006 any format by integrating a range RECOMMENDER: Ross Hardison Publications of note of bioinformatics tools and linking them out to various data ware- Last year in Current Protocols in houses. Galaxy lets users save and ers to verify derived results, and in Bioinformatics, Taylor published share every step of their analysis and general that if it isn’t transparent and a paper entitled “Using Galaxy to workflow with other users, and also reproducible, it isn’t science.” perform large-scale interactive data allows people to analyze multiple Taylor says it was his exposure to analyses,” which presented the Gal- alignments, compare genomic an- the disconnect between those de- axy interface to the bioinformatics notations, and profile metagenomic veloping computational tools and user community. The paper shows samples, among other tasks. those generating the data early in his how Galaxy can be used to help The bigger picture for Taylor is not career that set him on his present researchers find the top 100 protein- just to provide tools and infrastruc- crusade. “During the course of my coding exons in the human genome ture with projects like Galaxy, but PhD work, I came to notice how big with the most density of SNPs by also to facilitate a cultural change a gap there is between people who accessing Galaxy’s URL and follow- among biologists and computer sci- are experimentalists by training and ing a specific protocol. entists. “In the future, experimental people who are computational by and computational biology are only training, and how inefficient that And the Nobel goes to… going to become more intertwined relationship is both in terms of how and even inseparable,” Taylor says. people developing methods provide Taylor says that if he were to win “What I hope to see is a culture those methods to the community and a Nobel, he would like it to be for that absolutely requires rigorous people who want to use those meth- the discovery of some “new form of peer review of both aspects, that ods and what resources are available heritable information, without which understands that software used in a to them to actually analyze their own we are completely stumped now, but published analysis needs to be open, data,” he says. Taylor also believes which makes everything completely needs to be delivered with the sup- that his work is very timely due to obvious.” porting information to allow review- the growth in data generation with — Matthew Dublin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 29

Wolfgang Huber COMPUTATIONAL BIOLOGY

Pushing Statistics to the Limit

ne might wonder how he says. “It gives us the possibility Wolfgang Huber, a trained to watch single cells and single mol- theoretical physicist, ecules do their job. Right now most Ogot into bioinformatics. of the data that we have is population Blame it on math — and the serious averages,” he says. Another tool that amount of coding that physics PhDs would help is deep sequencing. But have to do in the course of getting managing and analyzing all that new their doctorates. Programming “is data is a formidable challenge; after pretty much part of [the] skills you all, finding people who are good at have to pick up when you do phys- math and also interested in biology ics,” Huber says. And in reality, he isn’t easy. “These people are very adds, what he’s doing with biological rare, very precious,” he says. data isn’t so far from what he originally trained to do. “In a way, physics Publications of note is describing nature with numbers, with mathematics, and I’m still doing In a paper published in Nature, that,” he says. Huber and colleagues looked at Huber, whose PhD degree is in TITLE: Group Leader, European genome-wide recombination events quantum stochastics, moved in- Bioinformatics Institute in S. cerevisiae, mapping crossovers, to computational biology during EDUCATION: PhD, University crossover-associated gene conver- a postdoc at the German Cancer of Freiburg, 1998 sion, and non-crossover gene conver- Research Center in Heidelberg, and RECOMMENDED BY: Janet Thornton sion across 56 yeast meioses. Their he now heads up a bioinformatics maps are the first high-resolution, group at the European Bioinformatics genome-wide characterizations of the Institute. There, he applies statistical scene as one of the first affordable multiple outcomes of recombination computing and analysis to every- ways to examine genomic informa- for any organism. thing from microarrays to automated tion on a large scale, Huber took his “We used tiling arrays to detect the microscopy. “We apply [it] to emerg- part-time interest to the next level. combination events at very, very high ing technologies in genomics, in par- Prior to his postdoc, Huber worked resolution — an unprecedented reso- ticular new sequencing, like Solexa as a programmer at the clinic affili- lution,” Huber says. Achieving this and 454 … and then automated ated with the University of Freiburg, near-base pair resolution required phenotyping of cells and possibly which led him to start taking classes Huber to bring in the big guns, model organisms using automated and learning about the new technol- statistically speaking. Like all ex- high-throughput microscopy.” On ogy. He began to see biology as “a perimental tools, he says, stats can be one hand, sequencing can yield a much more dynamic and exciting optimized, or tweaked, to make the huge amount of genotype informa- field,” which he compares to the state tool experimentally better and stron- tion, while on the other, imaging of physics in the early 20th century. ger. “We had to push the limits of can give “very subtle and interesting “Completely surprising discoveries statistical data analysis much further phenotype variation,” he says. “In are being made,” he says. than had been done before to achieve both cases, we’re really interested in this high accuracy of our genotype the relationship between genotype Looking ahead calls. If we had used existing meth- and phenotype.” ods, the data would have been much Huber’s interest in biology co- As for the future, Huber hopes tools too noisy,” he says. “It’s almost like incided, he says, with the emergence will continue to improve to allow him building a new telescope or a new mi- of the genomic era in the ’90s. With to see images across four dimensions, croscope. We can suddenly see things the Human Genome Project under- including space and time. Viewing that we couldn’t see before.” way and microarrays hitting the cells in real time is the ultimate goal, — Jeanene Swanson

30 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

Xudong Yao PROTEOMICS

From Signal Transduction to Cystic Fibrosis

t’s not every scientist who govern regulation of signal transduc- can successfully juggle basic tion. “We try to use a chemical method research with clinical studies, in addition to gas-phase reaction [to Ibut Xudong Yao has found enable] ultra-high specificity and a a way. His lab at the University of very high yield of certain ions,” he Connecticut has an ongoing col- says. “By doing this we can increase laboration with the Cystic Fibrosis the sensitivity by tens of times.” Foundation, but he also maintains an emphasis on the more fundamen- Looking ahead tal side with a focus on phospho- rylation and understanding signal Going forward, Yao says he hopes transduction. to “continue to strengthen our re- Yao came to the US in 1995 after lationship with the Cystic Fibrosis earning his bachelor’s and master’s Foundation.” That involves applying degrees at Nanjing University in new mass spec methods “to help China. He completed a PhD in 2000 find a cure of this disease,” he adds. at the University of Maryland, and Meantime, he will continue the focus stayed at the school for another few TITLE: Assistant Professor, on basic research as well, trying to years to carry out a postdoc with University of Connecticut figure out “how to increase the in- Catherine Fenselau. The Fenselau EDUCATION: PhD, trinsic sensitivity and selectivity of lab has a long tradition of combining University of Maryland, 2000 the analysis of those molecules,” he “chemistry strategies with mass spec- RECOMMENDED BY: says. He also expects that his lab will trometry to study biomedical prob- Catherine Fenselau move more in the direction of what lems,” Yao says. His goal there was he calls “pathway phosphoproteom- to work on approaches that would ics.” This concept could eventually allow scientists to perform “selective partnership with the group. help in the clinical realm as well, he analyses of certain numbers of pro- Through the collaboration with the says, noting that many proteomic tein targets in order,” he says, noting foundation, Yao’s lab uses “a mass biomarkers tend to be difficult cases that as proteomics advances, people spec assay to monitor the plasma for mass spec analysis. are looking for a greater level of con- membrane expression” of CFTR, the trol over how peptides or proteins are critical gene linked to cystic fibrosis. Publications of note targeted for analysis. His time in industry has given Yao But Yao’s path to UConn wasn’t a an awareness of the importance of Last year, Yao co-authored a paper direct one. He “took a detour,” he getting great tools out to potential entitled “Oxygen isotopic substitu- says — he headed to industry for a users, and he hopes that his work tion of peptidyl phosphates for mod- short time, working first at GeneProt with the assay for CFTR will be one ification-specific mass spectrometry,” and then at Millennium Pharmaceu- example of this. “Hopefully this can which was published in Analytical ticals. While he’s glad to be back in be expanded to related proteins,” he Chemistry. The paper reports “the academia, his time in industry was a says, “so that it can be applied to first method of isotopic substitution stroke of luck: through GeneProt, he personalized medicine.” of a nonbridging oxygen atom in pre- met Diana Wetmore, now a leader at On the basic research side, Yao and existing phosphates on peptides,” the Cystic Fibrosis Foundation and his team are busy trying to get at the which, according to the authors, Yao’s connection for establishing a sequence of phosphopeptides that solves “a long-standing, challenging issue in the sample preparation “Hopefully this can be expanded ... so that it can of phosphopeptides,” the abstract states. be applied to personalized medicine.” — Meredith Salisbury

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 31

Giselle Knudsen PROTEOMICS

From Detection to Drugs

iselle Knudsen wants to drug is used in patients. find a better way to detect proteins in cells. To Publications of note Gthis end, she is developing Raman spectroscopy, a detection Knudsen’s work on Raman spec- method based on how the sample troscopy was recently published in scatters light from a laser, for the Bioconjugate Chemistry. In it, Knud- life sciences, particularly proteom- sen and her colleagues were able to ics and cancer drug target develop- use their Raman spectroscopy-based ment. “It’s extremely sensitive. It’s technique to accurately and precisely going to enable us to quantify very quantify human GMP synthetase. In small ratios of two different protein the single-point determination mode, species at very low concentrations,” synthetase with mass ranging from she says. 1 μg to 1 ng could be measured with Knudsen, who originally trained as between a one and six percent error an enzymologist, made the switch to and as an imaging application with proteomics when she realized that a relative standard deviation of 16 looking at proteins in a vial doesn’t TITLE: Research Scientist, percent. necessarily reflect how those proteins University of California, San Francisco behave in a cell. “I realized that we EDUCATION: PhD, University of Looking ahead can do reductionist biology only so California, San Francisco, 2003 long. We have to start looking at RECOMMENDED BY: Charles Buck Knudsen hopes that Raman spec- what things actually do in the real trometry will be applicable in a clini- cell,” Knudsen says. Along with her cal setting. “The only reason I am postdoc advisor, Jo Davisson at Pur- numbers,” she says. working on this methodology is be- due University, who also trained in Once the technique is refined, cause I really want to use it. The next enzymology, Knudsen is adapting Knudsen plans to apply it to study- step is, once I get people to accept to a world where “enzymologists are ing the diversity of protein isoforms the method, I really want to start becoming proteomics experts and found in cells, especially cancer cells. solving problems. It’s going to have they are interested in classical phar- “We’re realizing in proteomics that to get much more clinical, I think,” macology — but they don’t call it it’s not just one enzyme that’s inside she says. that anymore.” of a cell, it’s actually probably 10 First, Knudsen is focused on or 15 different forms of the same And the Nobel goes to … working on Raman spectroscopy, enzyme. Each of those 10 or 15 dif- which she says is more sensitive ferent forms have different, unique Knudsen doesn’t approach her work than fluorescence-based detection functions,” she says. “In cancer biol- thinking about Nobel prizes — she methods and is competitive with ogy, for example, we want to be able looks at it as wanting to change the other detection methods used in bi- to target just one of those 15.” By way people do experiments, particu- ology. “I can measure the spectrum targeting that one protein, she says larly how they measure molecules, of these two species in the same scientists will be better able to define to be more accurate. “If I can be measurement. That means that I re- that protein as a drug target and thus recognized in the future for doing duce the noise, the background, so reduce the number of side effects or biomolecular detection, that would I can get very accurate and precise nonspecific effects seen when that be great,” she says. “But I see myself as being very spread among different “We have to start looking at what things fields, so I don’t know if that’s going to work for me.” actually do in the real cell.” — Ciara Curtin

32 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

Wei-Jun Qian PROTEOMICS

Step by Step, a Better Mass Spec

or Wei-Jun Qian, the of pancreatic islets could help de- appeal of a place like termine why diabetes patients fre- the Pacific Northwest quently lose these cells, and possibly FNational Laboratory even how to help recover them, he comes down to technology develop- hopes. He says he would also like to ment. “This place is really so technology- get involved in developing a cancer oriented,” he says, “it’s a great place biomarker discovery project. for me to integrate lots of different techniques.” Publications of note Qian has long been involved in developing ways to improve technology. A review paper in Molecular & Cel- Proteomics has always been known lular Proteomics that came out in 2006 for its difficulty with quantification, entitled “Advances and challenges in and that is one area where Qian liquid chromatography-mass spec- has spent a good deal of time. Par- trometry-based proteomics profiling ticularly for clinical studies, he says, for clinical applications” offers a good good quantification practices have overview of the hurdles yet to be been tough to come by. “Proteomics TITLE: Senior Scientist, Pacific overcome in the field, Qian says. is so complicated, so complex,” he Northwest National Laboratory Qian was lead author on a paper says, noting that practitioners must EDUCATION: PhD, University of published in the Journal of Proteome be able to detect proteins of very low Florida at Gainesville, 2002 Research in 2005. “Probability-based abundance in a sample for studies RECOMMENDED BY: Dick Smith evaluation of peptide and protein involving, say, a protein biomarker identifications from tandem mass for disease. spectrometry and SEQUEST analy- Qian’s goal is to marry the benefits In one of his main projects, Qian sis: The human proteome” reports of high-throughput biology with the is getting ready to analyze samples the findings of Qian and collabora- advantages of a more targeted ap- from hundreds of patients over many tors’ study of how to assess false proach. “I’m trying to link global time points to get a better grasp of positive rates in the identification of discovery with target validation,” he diabetes. “We initially spent almost peptides by analyzing three human says. This work relies on a triple- two years trying to work out the proteome samples. The authors note quadrupole mass spectrometer. Qian techniques” to prepare for this study, that false positive rates were higher says he also works a lot on chemistry he says. His next challenge will be to for peptides identified from human and labeling approaches to try to im- help determine “which protein is the plasma samples than for those identi- prove quantification as well. most interesting,” he adds. fied from human cell lines, and they At PNNL, his mandate is to use suggest new filtering criteria to im- mass spec-based proteomics and Looking ahead prove confidence in peptide calls. to develop new methods for applying the technology. The idea is to In the next few years, Qian says And the Nobel goes to … improve scientists’ ability to study that he will continue the diabetes post-translational modifications, cell work and expects to focus his tech- Qian says that he would feel that he signaling, and disease biomarkers nology improvement efforts specifi- had earned a Nobel prize if he could by finding ways to see proteins more cally on studying and understanding “really identify a protein [that was] a clearly and precisely. that disease. The proteomic analysis huge therapeutic target, or something resolving some sort of cure for a dis- “I’m trying to link global discovery with ease like diabetes — using proteomics, of course.” target validation.” — Meredith Salisbury

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 33

Shamil Sunyaev POPULATION GENETICS

A Better Approach to Interpretation

hamil Sunyaev’s inter- the different disciplines they cover. ests run the gamut. One “There’s so many nice projects, I of them is in mutations, think we just do too much,” he says. Swhich he studies from three different points of view: func- Looking ahead tion, evolution, and medicine — all without picking up a pipette. In his The field is moving very quickly, lab at Harvard Medical School, Sun- Sunyaev says. “This is what I’m bank- yaev is developing computational ing on: I think that we will have a lot and statistical tools to analyze muta- of genomic data and something will tions and genetic variations. Also, he come out of that or not come out [de- is developing bioinformatics tools to pending] on how it is interpreted,” deal with the coming sequencing and he says. proteomics data. In the 1960s through the 1980s, Sunyaev and his lab are working on Sunyaev says, there were a lot of nice methods to predict molecular func- analyses developed but there was no tion from sequence data. For this, data for them. Soon, he says, “the Sunyaev takes a comparative genom- TITLE: Assistant Professor, position will be reversed.” He expects ics approach and collaborates with Harvard Medical School that there will be an abundance of functional genomics groups. Then, EDUCATION: PhD, Moscow Institute data, and the bottleneck will be in- they also take a look at that same of Physics and Technology, 1997 terpreting it all. data with an eye toward evolution- RECOMMENDED BY: Peer Bork ary genetics and how the mutations Publications of note they see affect fitness. In particular, Sunyaev is interested in evolutionary the available data and try to learn A 2001 paper of Sunyaev’s in Human patterns and what happens to those population genetic models and then Molecular Genetics estimated that a variants over time. Finally, he col- simulate very large resequencing single human genome contains 1,000 laborates with medical geneticists to studies,” Sunyaev says. This will help deleterious mutations by examining analyze how these genetic variants indicate “what strategies are going to the effects that amino acid replace- affect phenotypes. be best — what is possible, what is ments have on protein structure and Sunyaev is also preparing for the not possible to do, and so forth, to function. In a more recent paper in coming glut of sequence data and inform future studies and to develop the American Journal of Human Genet- the information about rare alleles tools to be used for these studies,” ics, Sunyaev and his colleagues stud- that will be hidden in these. “Human he adds. ied the role of low-frequency genetic genome sequencing is becoming so Another objective in the Sun- variants in disease and found that 70 accessible that we will have many, yaev lab is developing computational percent of low-frequency missense many human genomes,” he says. “You methods for proteomics. One such alleles are mildly deleterious, mean- have very large amounts of data and project has Sunyaev comparing pro- ing that they are associated with a sequencing will discover very many tein interactions and protein com- loss in fitness. variants — and many of them will be plexes across yeast species. Another rare in the population.” is part of the SysCode consortium And the Nobel goes to... In his lab, Sunyaev is working on which has the goal of engineering developing methods to analyze those mammalian organs, but in a way Sunyaev would like to win for “a sequences and plan for upcoming that is informed by developmental model completely explaining the resequencing projects. “Right now, proteomics. inheritance of complex traits and the in this regard, we’re trying to do Sunyaev says the challenges fac- molecular architecture of the traits.” population simulations…to look at ing his lab include incorporating all — Ciara Curtin

34 WWW.GENOME-TECHNOLOGY.COM______DECEMBER 2008/JANUARY 2009

Raul Rabadan POPULATION GENETICS

Elucidating Evolution, Virus by Virus

t may be a far cry from elu- percent of its genome,” he says. “So if cidating the finer points of we take a mammalian example, that’s spacetime, black holes, and like comparing a mouse to a human, Iquantum mechanics, but Raul so we have an idea of how evolution Rabadan is thoroughly content with is working — population genetics, his decision to leave the world of mutation, and selection.” theoretical physics for a research In order to find the changes that post working on RNA viruses. Just take place over time in RNA viral two years ago, Rabadan was hard at genomes, which can run from 1,000 work publishing papers on string to 100,000 base pairs in length, he theory as a postdoc at the Institute and his fellow investigators have for Advanced Study at Princeton, developed algorithms capable of when he began to take notice of the large-scale comparative analyses of school’s new center for systems biol- human and avian viral genomes. ogy. “I started talking to a colleague Through such methods, they have of mine, another string theorist who demonstrated evidence supporting was working in biology, and found the hypothesis that the H1N1 strain that what they were doing was rather TITLE: Assistant Professor, of the influenza virus entered the interesting,” says Rabadan. “Then, Department of Biomedical human population before the actual I decided to collaborate with them, Informatics, Columbia University 1918 outbreak, possibly as early as and then at some point, I just de- College of Physicians and Surgeons 1910. cided to switch fields.” EDUCATION: PhD, Universidad Rabadan says he likes the fact Autonoma de Madrid, Spain, 2001 Publications of note that, from a basic scientific point RECOMMENDED BY: Bud Mishra of view, viruses are excellent mod- In a 2006, Rabadan published a els for understanding how living paper entitled “Comparison of hu- organisms work and evolve. “Even how they work is something very man and avian influenza A viruses if we sequence every human on important.” reveals a mutational bias on the viral the Earth, the question becomes, Rabadan’s current area of focus is genomes” in the Journal of Virology. In how can we deduce the history and the analysis of RNA viral evolution, it, Rabadan and his colleagues pre- the pressures? How do we deduce which happens at a much faster rate sented what he calls a very “nice and selection for some particular genes than many other model systems. simple idea” that aims to improve and how these genes are evolving in He and his colleagues are currently understanding of viral outbreaks. disease, given the data?” says Raba- working on ways to analyze thou- The aim of their research was to un- dan. “But with viruses, you can see sands of viral RNA genome datasets cover and characterize the changes a how they are evolving with time be- — with particular targets of HIV virus undergoes as it jumps from one cause they are evolving very fast. So and influenza — in order to better host to another — in this case, from I think viruses can give us a very understand their evolution and epi- bird to human — usually resulting in good understanding of evolution demiology. “We have a lot of samples, pandemics such as the 1918 influenza — not to mention they are burdens such as the 1918 flu, which, almost a virus. After the analysis of several to our society, and understanding century later, has changed almost 15 genomes of different viruses living in birds and humans, the researchers discovered that viruses evolving “Even if we sequence every human on the Earth, in different species’ host organisms the question becomes, how can we deduce the have very distinctive mutation patterns. history and the pressures?” — Matthew Dublin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 35

______

Rachael Thomas COMPARATIVE GENOMICS

Cancer in Dogs, Cats, and People

ogs and people aren’t cancer are intertwined. “By which I that different, especially mean,” she adds, “working out what if you take a long view is actually the trigger that causes the D— go back far enough transition from a benign, chronic and there’s a mammalian ancestor form of inflammation into full-blown common to both. That’s why North malignancy.” Carolina State University’s Rachael As she did in dog, Thomas is Thomas is studying dog lymphoma developing the tools to study genetic with an eye toward how it is similar variation in feline lymphoma. “My to human lymphoma, particularly hope is that in the next few years, focusing on genetic abnormalities I can develop this area of feline correlated with disease subtype. genomics so that ... we can actually “Human lymphoma and dog lym- really get a handle on some of these phoma effectively share an absolutely factors which are a big feature of hu- extraordinary level of conservation,” man cancers but for which there is Thomas says. no other feasible model that we can Currently, Thomas is focusing on study,” she says. developing resources so that she and TITLE: Research Assistant Professor, her colleagues can compare the ge- North Carolina State University Publications of note netic profiles of human and canine EDUCATION: PhD, University of lymphomas. She has made a high- Leicester, 2000 Thomas’s work on microarrays for resolution genomic microarray for RECOMMENDED BY: Barbara Sherry the dog genome was just published the dog containing a panel of genetic in Cytogenetic and Genome Research. markers that have been mapped back But her work on the dog genome goes to the dog genome. “We can now mans. “It [is] far easier for us to gen- back to her undergraduate days, and directly convert information we have erate large amounts of genomic infor- she is one of the many authors on obtained on chromosome abnormali- mation that we can actually translate the dog genome sequence assembly ties to establish, by looking at the back and forth,” Thomas says. paper published by Nature in 2005. genome sequence assembly, which “That is something that I will always genes are impacted by those genomic Looking ahead be proud of,” she says. abnormalities and, in turn, translate that back into the corresponding For the future, Thomas is looking to And the Nobel goes to … regions of the human genome to move beyond the dog to study lym- see whether the human and the dog phoma in the cat. In cats, lymphoma “What I would really love to be able counterparts of the same disease ac- is associated with inflammation, par- to do is ... translate our discoveries tually share the effects of same-gene ticularly in response to the feline in genomics into some form of tool frequency,” Thomas says. immunodeficiency virus. This, that really does represent a genuine, Dogs are a population of highly Thomas says, is also a naturally oc- meaningful advancement in cancer inbred animals that have predisposi- curring system to study the lympho- diagnosis, disease management, for tions to certain cancers, making their ma that people with HIV develop, both humans and veterinary spe- population easier to study than hu- as well as how viral infections and cies,” Thomas says. “That really exemplifies this whole ‘one medicine’ concept that we have, that the “We can now directly convert information we combination of those two fields has have obtained on chromosome abnormalities far more impact than just looking at them separately.” ... to establish which genes are impacted.” — Ciara Curtin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 37

______

Carey Lumeng TRANSLATIONAL RESEARCH

Investigating the Perils of Obesity

s a pediatrician, the resolution,” he says. As his lab gets University of Michigan’s up and running and starts collecting Carey Lumeng has been samples from patients — including Awatching the rise of obe- those who have undergone bariatric sity among children. Along with obe- surgery — and from different types sity come diseases such as asthma of fat tissue, Lumeng hopes to be able and diabetes, among others, but ex- to use high-throughput drug screen- actly why too much fat is so bad for ing and genomics. people is still not known. Lumeng suspects it has something to do with Publications of note inflammation. “There have been a wide variety of genomic studies that It was in the January 2007 issue have also validated the idea that of the Journal of Clinical Investigation inflammatory markers are strongly that Lumeng and his colleagues first associated with obesity as well as proposed their model of different diabetes,” Lumeng says. types of macrophage activation and Some of those screens found that how that activation is altered in obe- macrophages are a component of the TITLE: Assistant Professor, sity. In a Diabetes paper published inflammatory response, and other University of Michigan online in October, Lumeng starts to studies have shown that macrophages EDUCATION: MD/PhD, address the mechanisms behind this invade fat tissue. “I think the bulk of University of Michigan, 2000 by using flow cytometry, immuno- the literature now has demonstrated RECOMMENDED BY: Alan Saltiel fluorescence, and expression analysis. pretty strongly that … these macrophages actually [are] required to Looking ahead generate inflammation with obesity smoothly translated to people. and, in fact, if you get rid of them or “My lab’s going to be looking at Lumeng says that the next few years block their function, the mice don’t this in human tissue and, in ad- will accelerate how people under- get diabetes,” he says. dition, we’re going to be trying to stand the role of inflammation in But macrophages are also found in understand what regulates one type obesity, especially in diabetes. Al- other, normal tissues where they do of macrophage, the good macrophage ready, Lumeng says that some diabe- not cause problems. The question for example the M2s, and what regu- tes drugs that were thought to target there, Lumeng says, is: “Why is one lates the bad guys, the M1s,” Lumeng fat cells have been found to actually in one context maybe OK and in the says. focus on macrophages. He also says other context maybe bad for you?” One method that his lab is already there are more diabetes drugs in the Indeed, there are different types of using to study these macrophages is a pipeline that target inflammation. macrophages, M1 and M2, as Lu- new imaging approach. Fat, Lumeng meng and his colleagues published says, is difficult to cut and tends to And the Nobel goes to … a little more than a year ago. Lean auto-fluoresce. To get a better look, mice, he says, have M2 macrophages his team has been using confocal If Lumeng were to win, he hopes it and obese ones have M1 types, but microscopy on whole pieces of tissue. would be because he found a way to what triggers the switch between the “It just lets us get a depth of imaging stop the negative effects of obesity by types is not yet known, nor is it clear that looks at all the different cells in addressing inflammatory changes. whether the findings in mice will be three dimensions at a much higher “Clearly this is going to be a huge issue in the next decades because all “These macrophages actually [are] required to the obese children are going to become obese adults,” Lumeng says. generate inflammation with obesity.” — Ciara Curtin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 39

Bridget Wagner TRANSLATIONAL RESEARCH

Large-Scale Screens to Study Diabetes

unning large-scale they produce insulin, they act like a chemical screens isn’t beta cell, but they’re a poor substitute easy, even if you’re at a for an actual beta cell.” Rworld-class facility like Wagner says that while current the Broad Institute. As a research screening technology works well, fellow at the Broad’s chemical her work would be greatly acceler- biology program for four years and ated with improved culturing tech- now the group leader for pancreatic niques for pancreatic islet cells to cell biology and metabolic disease, bring that process into the high- Bridget Wagner spends most of her throughput realm. The ideal sce- days optimizing the basics of her nario, she says, would involve being small molecule screens, with an able to specify cell identity on com- eye on drug targets for type 1 dia- mand. “The same way that geneti- betes. cally it’s now possible to turn a hu- Her research focuses on finding man skin cell into an iPS cell, we’d ways to stop or slow down the de- love to have small molecules [where struction of pancreatic beta cells, we] can say, ‘All right, you’re start- which, in diabetes, cease producing TITLE: Group Leader in Pancreatic ing out to be a pancreatic exocrine insulin and die off. Wagner’s ap- Cell Biology and Metabolic Disease, cell, but now you’ll be a beta cell,’ or proach takes advantage of large-scale Broad Institute of Harvard & MIT vice versa,” she says. biology tools and the Broad’s exten- EDUCATION: PhD, Harvard University, sive screening facility. “What we’re 2003 Publications of note trying to do is see if we can identify RECOMMENDED BY: Stuart Schreiber compounds that can be used to pro- Her work promises much clinical mote beta cell growth and health application. In a collaboration with in the case of type 1 diabetes,” she technological foci,” she notes. fellow Broad member Vamsi Mootha says. Wagner says she’s lucky to have the this year that was published in Her approach to stimulate the body Broad’s resources, which include an Nature Biotechnology, Wagner used to regenerate beta cells is three- enviable screening facility. “There’s a cell-based assays to screen almost pronged. The first tack is to “stimu- very large push towards synthesiz- 2,500 small molecules to probe late the beta cell itself to divide,” she ing libraries of compounds here that mitochondrial gene expression pat- says, which would restore insulin are all slightly structurally related to terns. What she found was, among production. The second is to try to each other, and that gets us a little bit other things, cholesterol-lowering prevent cell death in the first place closer to understanding why some of statins resulted in mitochondrial by identifying “compounds that the chemistry is having an impact in toxicity. “It’s important because sta- could overcome the autoimmune- the cells.” tins cause a kind of rare but very based attacks on beta cells,” she One of the toughest challenges is serious muscle myopathy as a side says. The third method is through identifying a positive assay readout effect,” she says. “trans-differentiation of other cell to serve as a control. “It’s often useful types in the pancreas.” To this end, if you already have a compound that And the Nobel goes to … her lab develops cell-based assays does what you want or a particular to observe different aspects of beta cell culture condition that mimics As for the Nobel, Wagner would cell function and health, and then the state that you want to have,” she like to take her current research performs screens with small organic says. Another hurdle is finding a good focus all the way. “I would think synthetic compounds. “All three of model for the beta cell. “There are a for curing diabetes, but that’s fairly these approaches use high-through- number of mouse cell lines, called in- ambitious,” she says. put screening as one of their main sulinoma cell lines,” she says, “[and] — Jeanene Swanson

40 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

Charles Schroeder TRANSLATIONAL RESEARCH

‘Cells In, Disease Out’

oming from a chemical “It was a lifelong learning for him. It engineering background, wasn’t just turning the crank or doing the University of Illi- the next sort of incremental thing. Cnois at Urbana-Cham- Everything he approached, he tried paign’s Charles Schroeder also to make his mark on and do in a wanted to do something practical for revolutionary type of way,” he says. human health. He is now developing a microfluidics-based tool to trap Looking ahead single DNA molecules so they can be genotyped. “The overarching goal of Schroeder is encouraged by the this project is to develop an integrat- current explosion of genome-wide ed microfluidics device ... where we association studies that are pinning take cells in and we get a genotype genes to disease. But he says this is or some information about disease only the beginning. He hopes that on the output,” Schroeder says. “It’s the next few years will bring more cells in, disease out.” detailed studies and resequencing of The microfluidics tool he and his putative disease genes and investiga- lab are working on traps and stretch- TITLE: Assistant Professor, University tion into rare alleles. “I view what’s es single DNA molecules using het- of Illinois at Urbana-Champaign been done — while they are really erodynamic, or flow, forces. “Using EDUCATION: PhD, Stanford interesting and amazing studies — this approach, we have a really nice University, 2004 [as] almost, at this point, proof-of- way to just stretch out and set our RECOMMENDED BY: Alan Guttmacher principle,” Schroeder says. He says mass-trap for linear analysis of their that researchers need to look beyond backbone,” Schroeder says. SNPs and study how copy number Once the DNA molecule is held stage in my career, [the challenge is] variations and larger rearrangements by the device, a bit of biochemistry basically getting a good momentum affect human health. comes into play. The scientists add in my own research group,” Schroeder fluorescent, sequence-specific DNA- says. His research covers a variety Publication of note binding proteins so the DNA se- of fields and his lab has to have the quence can then be determined. “Just proper mix of expertise. “As a man- Much of Schroeder’s current work like a barcode sequence, you can read ager or a PI, it’s doing the right hiring deals with genotyping, but his back- out the position of these fluorescent and making sure that your group ground is in single-molecule research. probes along the stretch of the DNA will have the skills that it needs to A 2003 Science paper from his gradu- molecules,” Schroeder says. be successful in an interdisciplinary ate career typifies his earlier work. By using techniques from single field,” he says. “That’s a really nice demonstration molecule analysis, biochemistry, and Schroeder has learned persever- of a polymer physics study [and] this physics, Schroeder and his group ance, in its many forms, from one of manipulation of single DNA chains, are developing a novel tool. “We his graduate school mentors, Steven or DNA chains at the single molecule really are doing some new technol- Chu. One of Chu’s lessons was that level,” Schroeder says. ogy development, so there are some “there [is] more than one way to significant barriers to overcome,” he solve a problem,” Schroeder says. And the Nobel goes to … says. “Whenever you do something “You can’t get discouraged if the first for the first time or try to figure out or second way doesn’t work.” Schroeder would like to win for a new technology, it’s challenging,” Schroeder says he has also been developing “a technology that would he says. inspired by Chu’s career trajectory; advance human health in some major Another challenge, though, is get- Chu began as an atomic physicist way.” ting the projects underway. “At this and now focuses on pure biology. —Ciara Curtin

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 41

Gad Getz TRANSLATIONAL RESEARCH

The Physicist Who Tackled Cancer

ad Getz was a physi- which are later,” he says. Eventu- cist with biology envy. ally, he hopes to gather enough data After earning degrees in to begin applying population genet- Gphysics and mathematics methods to tumor sample col- ics, he realized that he was interested lections, but he believes that will in applying some of these concepts, require a breakthrough in single-cell such as statistical mechanics, to the interrogation abilities. “We still don’t biology realm. necessarily have the technology to do He started out “doing cluster- all of these things,” he says. He adds ing of protein structure and then that integration of large-scale data gene expression data” and eventu- sets remains a problem; dealing with ally found himself on a path to the different modalities of data could be- Broad Institute, where a postdoc with come more and more arduous unless Todd Golub landed him squarely in this challenge is faced. the middle of microRNA research, among other projects. By last year, Publications of note Getz became head of the cancer genome analysis group at the Broad TITLE: Head of Cancer Genome Two papers in particular sum up and had established himself as a Analysis, Broad Institute Getz’s more impressive endeavors. full-fledged member of the systems EDUCATION: PhD, Weizmann In “Assessing the significance of biology community. Institute of Science, 2003 chromosomal aberrations in cancer: Today, Getz’s goal is to combine RECOMMENDED BY: methodology and application to gli- as much data as possible to paint a Alan Guttmacher oma” in PNAS, Getz was a co-lead au- comprehensive picture of cancer. He thor describing GISTIC, or Genomic gathers information from sequence Identification of Significant Targets reads, copy number, gene expres- suspects that it won’t be the individ- in Cancer, the algorithm he devel- sion, methylation status, genome- ual genes as much as the pathways oped to scan data from tumor cells wide analysis studies, and more. All they belong to that could be the and generate predictions of which of that gets fed into GISTIC, an crucial factor in cracking the cancer mutations are cancer-inducing in- algorithm Getz started writing as a puzzle. stead of caused by the cancer. postdoc to scan through reams of Getz is a member of the Cancer In the other paper, Getz was part cancer data and pick out the muta- Genome Atlas consortium, for which of the Cancer Genome Atlas project, tion patterns that mark the onset of he’s continuing his past work of “de- which published findings in Nature cancer from all the other complex veloping these methods that take all this fall regarding its study into lung changes that take place in a tumor of these genomic data and come out adenocarcinoma. Researchers found cell but do not actually cause cancer. with biologically significant events,” 26 genes that appear to be highly Getz refers to this as “distinguishing he says. linked to the onset of this type of the drivers from the passengers” on lung cancer, a significant increase the road from normal cell to tumor. Looking ahead in the number of genes suspected to The algorithm is designed to analyze play a role in the disease. all the data, looking for mutations Getz hopes to take his knowledge occurring at a higher frequency than of cancer analysis and put it to work And the Nobel goes to … you’d expect by chance, he says. across the tumor development pro- But picking out cancer-linked genes cess. He will use mouse models to This question doesn’t delay Getz at is just a stepping-stone to the real study several phases of cancer, sam- all. His dream achievement? “Curing goal of figuring out which pathways pling tumors over time to find out cancer,” he says. are implicated in tumorigenesis. Getz “which events occurred first and — Meredith Salisbury

42 WWW.GENOME-TECHNOLOGY.COM______DECEMBER 2008/JANUARY 2009

______

The Tree of Life The Guardian Discovering Biology in a Digital World Newsweek oinformatics Zen BBC News DNA and You Mike the Mad Biologist Buried Treasure Publi brary of Science Next Generation Sequencing business|bytes|genes|molecules Computationa ology and Evolution Computational Biology News Free Genes Freelancing Science Slate Genomeboy Microarray and Bioinformatics Bitesize Bio Eye on DNA Science The Seven tones Genomics, Evolution, and Pseudoscience In the Pipeline Life as a Healthcare CIO rtyn Amos Technology Review Bayblab Medgadget Microbial Genome News Proceedings o National AcademiesM[iYWd of Science The DNA Testing BlogDWjkh[ My Biotech Life Nascent Nodalpoint ics! Omics! Economist The Genetic Genealogist Genome Biology Patent Docs peanutbutte Periodic Tabloid PolITiGenomics Adventures in Ethics and Science evolgen Sandwalk Respectful Insolence savas:weblog ScienceRoll Synthesis Discover The Evilutionary Biologist The Gene Sherpa The Personal Genome International Herald Tribune Cognitive ily Gene ExpressionWdZW\[m What You're Doing is Rather ej^[hi Desperate Yahoo! News Your Bones Got Little Machine FinchTalk Genetic Future VentureBeat Epidemix Genomicron Genomics Revolution Forbes Mailund on the Internet Adaptive Complexity On Genetics The Daily nscript Nature A Forum for Improving Drug Safety Highlight Health LA Times PredictE og Yann Klimentidis' Weblog Flags and Lollipops Information on Genes Retail Genomics e LoomieoekZedÊj^Wl[je$ Aetiology Genome Research Terra Sigillata Fast Company Uncertain Principles Pharyngula Epigenetics News Pure Pedantry New York Times Living the Scientific Life (Scientist, Interrupted) Biocurious Framing Science Boston Globe Science Commons uicyte Notes Public Rambling Sciencebase Web 2.0 and Semantic Web for Bioinformatics he Spittoon Three Quarks Daily The Scientist Wired MassGenomics Wall Street Journal ?\oekedbo^Wl[\_l[c_dkj[iWZWo" ^[h[Êim^Wjoekd[[Zjeh[WZ$ J^[:W_bo IYWd Xhek]^jjeoekXo=[dec[J[Y^debe]oEdb_d[ Blogs Podcasts We comb through more than 60 blogs to Plug in for the Weekly Scan, our recommend the most interesting posts. podcast of news and blog highlights.

Papers Polls Highlights from journals such as PLoS We pose a new question each week. Cast Biology and PNAS, plus weekly reports of your vote and see what your peers think the news and papers in Nature and Science. about issues of the day.

Mass Media Young Investigators Can’t get to every major newspaper and Don’t miss the young investigator of the magazine? We scan the mainstream media week, chosen through recommendations to keep you up on the news you need. from leading scientists in the field.

H[]_ij[h\ehoekh\h[[:W_boIYWd8kbb[j_d

Wjmmm$][dec[#j[Y^debe]o$Yec$______

Len Pennacchio REGULATORY ELEMENTS

Finding Function in Dark Matter

en Pennacchio takes ge- lenge for his field to be a techno- netic variation seriously. logical one. While JGI has next-gen As head of the programs sequencers up and running — “and Lfor genetic analysis and they’re exponentially more powerful genomic technologies at the US De- than the old capillary sequencers,” partment of Energy’s Joint Genome he says — it’s still too expensive and Institute and a senior staff scientist at labor-intensive to get individual hu- Lawrence Berkeley National Labora- man genome sequences. tory, Pennacchio focuses on genetic And even with all that sequencing variation, especially of the regula- data, the true power resides in func- tory parts of the genome. Specifically, tional testing. “I think now it’s time he looks at how noncoding regions to try and figure out, does noncoding called enhancers promote gene ex- DNA play a large role in disease and pression during development, and what makes each of us who we are, how this “dark matter” of the genome or is it involved in protein encoding might play a role in disease risk. parts of the genome?” he says. In the He uses a combination of sequenc- next five years, Pennacchio predicts ing and comparative analysis to pin- TITLE: Senior Staff Scientist, that research will move toward func- point possible enhancers, and then Lawrence Berkeley National tional analysis of noncoding DNA to goes one step further into functional Laboratory; Head, Genetic Analysis better understand the role of regula- analysis. “We’re very interested in and Genomic Technologies Programs, tory elements in human disease. testing sequences in animals,” Pen- Joint Genome Institute nacchio says, “so we make our pre- EDUCATION: PhD, Stanford Publications of note dictions and then immediately go University, 1998 in and test the sequences to see if RECOMMENDED BY: Eddy Rubin In 2006 Pennacchio was first author they can turn on gene expression on a Nature paper that characterized in mice.” the in vivo enhancer activity of a large Using a beta-galactosidase reporter throw next-gen sequencing at the group of noncoding elements in the gene, he’s determined the activity problem. Pennacchio, who got his human genome that were conserved of nearly 1,000 potential enhancers PhD with Rick Myers and did a across humans and pufferfish or ultra- in humans. While most of the ele- postdoc in Eddy Rubin’s lab, still conserved across humans, mouse, ments were selected based on their devotes most of his own research and rat. Using his transgenic mouse conservation with other vertebrates, time to health-related issues. “We’re assay, he found that 45 percent, or 75 conservation alone doesn’t say what very interested in sequencing indi- of the 167 conserved segments, were the gene is doing. “You can look at vidual genomes and trying to un- enhancers of gene expression during that sequence and try and predict derstand what are sequence variants embryonic development, and that the until you’re blue in the face, but and how do they contribute to hu- majority of the 75 enhancers directed you’ll never most likely have any man disease,” he says. “We also set expression to various regions of the real clue as to what it’s doing” until up a pipeline so that we can brute- developing nervous system. functional analysis is performed. In force sequence genes in thousands the end, animal readout lets him of people [to] better understand the And the Nobel goes to … see when and where a given gene is relationship of human variation to expressed. His lab primarily focuses disease phenotypes.” Pennacchio says he’d like to win on the developing brain and nervous the Nobel for “trying to drive func- system. Looking ahead tional insights into the noncoding Linking genetic variation to disease portion of the genome.” is a looming goal, and he hopes to Pennacchio sees the biggest chal- — Jeanene Swanson

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 45

Zhaolei Zhang REGULATORY ELEMENTS

Where Collaborations Are King

haolei Zhang remembers attributes of yeast, with a specific very clearly what set him eye on evolution, transcription, non- on his course to becom- coding RNAs, and protein-protein Zing a scientist. He grew interactions. The broad goal is to be up in China in the early 1970s, able to pinpoint function of specific a time when the country was just genes and proteins to understand not “opening up to the rest of the world,” only what they do, but also how they he recalls. At the time, being work together. Zhang, who began involved in science was suddenly very at Toronto in the fall of 2004, has exciting and honorable, he recalls. appointments in both the medical “Nobel prize winners were national research and in the medical genetics heroes,” he says. He and many of his and microbiology departments. friends wound up pursuing scientific degrees. Publications of note After majoring in biophysics, Zhang packed his bags and set out for Cali- Earlier this year in the Genome fornia, where he earned his PhD Research journal, Zhang and his col- with Sung-Hou Kim while studying TITLE: Assistant Professor, leagues published a paper called “The protein crystallography and struc- University of Toronto extensive and condition-dependent tural biology. “I thought it was a EDUCATION: PhD, University of nature of epistasis among whole- really cool idea to use chemistry to California, Berkeley, 2000 genome duplicates in yeast.” He says study proteins,” he says. His research RECOMMENDED BY: Mark Gerstein that the study, which included a with Kim involved determining the number of authors from a range of structure and functional mechanism collaborating labs, involved looking of complexes of membrane proteins putational techniques and focused “at how duplicated genes in yeast that play a role in cell respiration. He on pseudogene evolution as well as can rescue each other in stress and was particularly involved in a project genome annotation. other conditions.” One method of to establish the structure of a specific Today, Zhang has his own lab at analysis in particular used protein cytochrome complex. the University of Toronto, where the interaction data to determine the In 2001 he packed up and headed spotlight is on regulatory elements functional overlap between epistatic to Yale University, where he complet- as well as yeast genetics and finding and non-epistatic genes. ed a postdoc with Mark Gerstein and computational ways to understand got his introduction to yeast genetics. the organism better. Zhang says his And the Nobel goes to … “I really enjoyed my time in Mark’s is a “dry” lab, but that he has made lab,” Zhang says. The timing couldn’t a point of establishing collaborations Were he to be honored with a No- have been better: “It was at the time with scientists in experimental labs bel one day, Zhang says he hopes the genome age started to emerge.” to put his computational work to it would be for “finding a cure for During the three years he spent in the test. He and his team are inves- AIDS.” HIV itself is a fairly small Gerstein’s lab, Zhang learned com- tigating the genomic and proteomic organism, he notes, and with the amount of money being poured in- to AIDS research from a variety of Zhang’s Genome Research paper, a study different funding organizations, he believes that this should be a trac- with a number of collaborators, looks “at how table problem. “I think it’s going to duplicated genes in yeast can rescue each happen in the next 10 or 20 years,” he says. other in stress and other conditions.” — Meredith Salisbury

46 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

Laura Elnitski REGULATORY ELEMENTS

The Functional Perspective

aura Elnitski will tell you she says. She expects that each cell that her early-career suc- type will have its own signature cess comes from luck, but panel of epigenetic markings, and Lobservers might notice that being able to use next-gen that her status as a young but highly sequencing will put scientists several regarded investigator at the National steps closer to being able to figure Human Genome Research Institute out cell identity and how the genome stems instead from her hard work is regulated. She and her team are and ability to balance backgrounds already looking into methylation of in cell biology and computational promoter regions and how that phe- biology. nomenon is linked to tumor cells. Elnitski began her studies at Penn Elnitski is also eager to move from State, where she earned her PhD what she calls the “linear perspective working in the molecular and cel- of the DNA” toward a more three- lular biology department with Ross dimensional look at what’s going on Hardison and followed up there in within the cell — but that’s going to a computationally focused postdoc be a very significant effort, she says. with Webb Miller. As a member of TITLE: Investigator, National Human “I won’t get there by myself.” Miller’s group, Elnitski helped build Genome Research Institute a computational approach to model- EDUCATION: PhD, Pennsylvania Publications of note ing genome regulation. Using a pair- State University, 1998 wise alignment between human and RECOMMENDED BY: Elaine Ostrander In a Genome Research paper from mouse, the algorithm would “look at June entitled “Detection and charac- the entire genome and predict which terization of silencers and enhancer- regions looked more regulatory and been a member of the consortium blockers in the greater CFTR lo- which looked more like neutrally for a number of different efforts. cus,” Elnitski and her colleagues evolving sequences,” she says. One project analyzes bidirectional demonstrate what she refers to as In 2005, Elnitski headed to promoters, which involves a lot of novel regulatory elements — that NHGRI, where she studies noncod- annotation but also may help sci- is, negative regulatory elements that ing functional genomic elements. entists get a handle on tumor sup- have been undercharacterized so far, “The idea is to discover them and pressors, since these promoters have she says. She is involved with the then to understand how the dis- been linked to regulation of these ENCODE consortium on the project ruption of their sequences relates suppressor genes. In another project to assess and annotate negative regu- to human disease,” she says. In her for ENCODE, Elnitski and her team latory elements. lab, she and her team are using both are studying negative regulatory ele- computational and experimental ap- ments by developing “functional as- And the Nobel goes to … proaches to track various regulatory says [and] screening sequences to elements — such as promoters or ex- find more of them,” she says. Were she to be preparing for a flight onic splicing enhancers — with the to Sweden, Elnitski says she hopes goal of better understanding whole Looking ahead her accomplishment would be “hav- classes of them. With that informa- ing some impact into understanding tion, she could look for “similarities As her work ramps up, Elnitski says the molecular mechanisms of cancer. in them or features that we can capi- she’d especially like to “tie in the epi- I think that ultimately that would be talize on to use for future prediction genetic modifications on the DNA or a gift to the medical community and and annotation,” she says. histones to try and understand what in its own way it would be a very Her work is a natural fit with the are the characterizing features of each important thing to me personally.” ENCODE project, and Elnitski has of these types of functional elements,” — Meredith Salisbury

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 47

Careers PROFESSIONAL LIFE

Steps to Start Your Career Experts from academia and industry offer advice to make your career path as smooth as possible. By Meredith Salisbury

Advanced degrees activities, whether it’s programming company doesn’t want to hire some- or certain types of statistics, and you one who will get bored quickly and Is a PhD necessary or a waste of can demonstrate that skill time and leave. “They want someone who can time? Would I be better off hav- time again, then you don’t necessar- do that job on a long-term basis,” she ing the years of work experience ily need the PhD.” Still, he notes, not says. “Turnover is really the biggest instead of investing those years having it can limit your career path concern.” in the degree? or make it harder to get your foot in the door. Are universities overproducing If your goal is to be in academia, this PhDs? Is that increasing grant is simple: a PhD is a requirement. But What are the most valuable ad- competition? if you’re looking to work in industry, vanced degrees for this field? there’s more nuance to the issue. “In “When I was in grad school 10 a lot of places, people don’t get hung Jason Liu, director of business years ago we were already over- up on degrees and you rise to your operations at Applied Biosystems, has producing PhDs,” Liu says. “I don’t own level,” says Michael Finney, a a PhD and an MBA — a combina- think the situation has changed that co-founder of MJ Research who now tion that he finds very valuable and much.” Combine that trend with the runs Finney Capital. “I know several sees as a trend in the community, dwindling grant funding available people who had no graduate degree especially as more universities offer and you’ve got some stiff competition at all who did just fine. But you have joint PhD/MBA programs. Having an on your hands, he adds. to be better to do that.” MD/PhD or even just an MD is also The PhD serves as evidence that you very useful, he says. The MD could The job search “have the ability to work towards a especially help if you have an interest long-term goal,” which can give com- in the clinical diagnostics industry, I’m searching for my first job, and panies more confidence in a person, he adds. I don’t have many publications. Finney adds. And there’s a problem What do I do? with just getting a master’s degree: Do companies avoid hiring PhDs “A number of places give master’s as for positions that are advertised That’s a question Wallace hears all kind of a booby prize for people who as requiring a master’s? the time, and she says often trouble dropped out of a PhD program,” he arises because scientists may feel says. If you went through a degree This can indeed be the case, says uncomfortable “selling” themselves program with the specific aim of Angela Wallace, a recruiter with in the job search process. It doesn’t getting a master’s, you should find Affinity Scientific. In some cases, pay to play it close to the vest in these a way to point that out so potential it’s because the group leader is not situations, she says. “If they are truly employers don’t simply assume you a PhD, and the company might be interested in the job when they walk couldn’t cut the PhD, he adds. “concerned about … having someone out of the interview, they should let Chris Bouton, computational biol- with a more senior degree report to the interviewers know.” As for a lack ogy group leader at Pfizer, says that them,” she says. Generally, though, of publications or experience, make a PhD isn’t required in industry: “If the situation is simply that the job sure your résumé is as specific as you’re very skilled in certain types of itself isn’t as challenging, and the possible, and don’t assume it’s safe to

48 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

skip over technical details. The first McGill University. But balance that says, then it’s time to start looking for pass of résumés for a job opening with loyalty to your postdoc — you another position. might be done by an HR person who don’t want to leave your PI high and doesn’t have a scientific background, dry by ditching early. Dewar passes Academia v. industry so you’ll need to market yourself well on advice that has served him well there, too. in his career: “The best training for I’m in academia and would like to Anything you can do to demonstrate your next job is how you act in your pursue a career in industry. Where your skills will help, says Bouton. If present one,” he says. This can help do I start? you’re applying for a bioinformatics establish that “you do good work, position, for instance, don’t just talk you can be trusted, you do well with Make sure you highlight any work about the classes you’ve taken in that other people.” you’ve done where skills you’ve area — try your hand at building a acquired would be transferable to the small database or website to show Is it better to be research-track at job you’re applying for, says Wallace. potential employers that you have a well known institution or tenure- If you’re considering a job in drug the ability and follow-through. track at a lesser-known one? discovery at a pharma or biotech and some of your research has involved The conventional wisdom is that That depends on your own career working with drug candidates or dis- you get the biggest promotions goals, says Dewar. He warns against covery technologies, point that out. and raises by changing jobs, but going someplace so small that there’s Also, it pays to know the dif- is that still advisable given a bad not a core group of scientists in your ferences between academia and in- economy? What are other avenues field already there; you’ll need access dustry before you make the switch, to getting a promotion or raise? to good people and technologies, Finney says, to avoid a “rude awak- after all. But going to a lesser-known ening” later. Industry scientists lack This depends on the scientific area place doesn’t mean the community the “proprietary ownership of a proj- someone’s involved in, says Wallace. will lose track of you — establish- ect” that academics are used to; they There are some skill sets that are just ing collaborations with colleagues at can be moved from project to project so hard to find that people who have other institutions can help keep you regardless of their own interests, he them can move anywhere, anytime. connected. “I don’t think you have says. On the bright side, he adds, If you would like to stay with your to be from Broad, Baylor, WashU, industry scientists usually enjoy bet- employer but are hoping for a pro- or U Washington to be successful,” ter hours, which can be more com- motion, take on the burden of laying he says. patible for family life. out goals that would be valuable to Liu says if you decide you want the organization; talk to your boss How do I know when it’s time to to go to industry, do it as early as about them, and then establish them leave my job and go somewhere possible. “From the industry stand- as milestones for your own devel- else? point,” he says, “the longer you’ve opment. Certain milestones should stayed in academia, you will have a be tied to a raise or a promotion. First things first, says Wallace: ask harder time to adjust to the industry Otherwise, it’s too vague — and yourself why you’re thinking about setting and pace to the R&D work- that makes it easy for an employer to leaving. A number of issues — such flow.” Liu went straight from his PhD push off these benefits. “Giving very as feeling unchallenged or becoming to working at a company, skipping a clear expectations for time periods interested in another aspect of busi- postdoc. and milestones is definitely the most ness or science — may be solved effective way to negotiate a promotion simply by talking to your manager If I go to industry, is it possible to or salary increase,” Wallace says. and asking for new or different re- return to academia? sponsibilities. If that doesn’t work, I’m a postdoc. At what point or if you’ve “found that the culture It may not be easy, but Bouton should I be looking for a faculty or the people … is not a fit,” Wallace says he’s certainly seen many people position? “You should always, in a sense, be “The best training for your next job is how looking,” says Ken Dewar, an associate professor of human genetics at you act in your present one.”

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 49

Consider taking a management class or two at a at a local college, or at least pick up some books of advice from the busi- local college, or at least pick up some books. ness literature. If you’re looking to move to another area of the company, such as market- make the leap back. If you think you The business side ing or business development, Finney might want to move to academia at recommends asking your boss for re- some point, it’s always a good idea to How do I make the transition from sponsibilities in that area. “If they’re keep publishing, “no matter whether the research side of my organiza- a good boss, they want to see you your employer values publications tion to the business or manage- succeed and they want to help you or not,” he says. When it’s time to ment side? out,” he says. make the move, consider a transi- ABI’s Liu accomplished this by tional step such as a core lab, which This isn’t as tough as it might seem, earning his MBA through a part-time is more industrial than academia says Finney. Start by talking to your program, a path he recommends to but more academic than industry. boss and getting someone to report to others. He says earning the degree “It’s certainly easier for somebody you — a lab technician, for instance, while working was a challenge, but coming out of industry to get a job who can help with your projects. helped him appreciate the business at a core facility,” Bouton says. Liu If that goes well, you’ll get more lessons in a real-world setting. N adds that he’s seen people manage reports, and soon enough it will this by moving back to an academic be clear to your company whether The content here is excerpted from postdoc position, and using that as a you’re good as a manager. Consider Genome Technology’s annual salary stepping-stone to the faculty path. taking a management class or two survey, published in July/August.

______

Grant Opportunities A number of funding agencies and other organizations offer grants targeted speciﬁcally at scientists who are just beginning their careers. By Jeanene Swanson

ORGANIZATION: The National impact prostate cancer research, ORGANIZATION: Alzheimer’s Science Foundation preferably in a clinical or translational Association AWARD: $400,000 over ﬁve years, setting. AWARD: As much as $100,000 total minimum award CONTACT: for up to two years DETAILS: The NSF Faculty Early www.prostatecancerfoundation.org DETAILS: The Alzheimer’s Career Development Program Association New Investigator supports junior faculty who exemplify Research Grant Program funds young the role of teacher-scholars. Women, ORGANIZATION: Infectious Diseases investigators with less than 10 years of minorities, and people with disabilities Society of America Education and research experience but who are not are encouraged to apply. Research Foundation and the National postdoctoral fellows. CONTACT: www.nsf.gov/funding Foundation for Infectious Diseases CONTACT: www.alz.org Joint Research Awards AWARD: $30,000 per year for two ORGANIZATION: National Alliance years ORGANIZATION: Pew Scholars for Research on Schizophrenia and DETAILS: The Wyeth Young Program in the Biomedical Sciences Depression Investigator Award in Vaccine AWARD: $70,000 per year for up to AWARD: $30,000 per year, for up to Development provides funding for four years two years outstanding research in vaccine DETAILS: The Pew award funds DETAILS: NARSAD’s Young development, either through clinical researchers with a full-time Investigator Award Program provides or laboratory investigation. The appointment as an assistant professor, support for promising young candidate must have a demonstrated or equivalent, who have not held that scientists in neurobiological research. commitment to vaccinology as a position for more than three years and Basic and or clinical investigators career. who are interested in basic or clinical are supported, but research must CONTACT: www.idsociety.org biomedical research. be relevant to serious psychiatric CONTACT: www.futurehealth.ucsf. disorders such as schizophrenia, ______edu/pewscholar.html mood disorders, anxiety disorders, ORGANIZATION: Office of Naval or child and adolescent psychiatric Research disorders. AWARD: As much as $170,000 ORGANIZATION: The McKnight CONTACT: www.narsad.org/research/ annually for up to three years Foundation ______apply/young/ DETAILS: The ONR’s Young AWARD: $75,000 annually for three Investigator Program funds early- years career scientists interested in basic DETAILS: The McKnight Scholar ORGANIZATION: Prostate Cancer and applied life science research, Award is open to young scientists, Foundation especially in marine life science, typically one year into their faculty AWARD: $75,000 per year for three neuroscience, biorobotics, and positions but not more than four years biosensors. years, who study learning and memory DETAILS: This funding program CONTACT: www.onr.navy.mil disorders. supports early career prostate cancer CONTACT: www.mcknight.org researchers who are doing high-

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 51

ORGANIZATION: Arnold and Mabel pharmaceutical industry, including supports academic research by young Beckman Foundation health outcomes, informatics, scientists in mass spectrometry. Open AWARD: $300,000 over three years pharmacology/toxicology, and to academic scientists within four DETAILS: The Beckman Young pharmaceutics. years of joining a tenure-track faculty Investigators Program supports CONTACT: www.phrmafoundation.org position or equivalent in a North Amer- chemists and life scientists on the ican university. tenure track at academic or nonprofit CONTACT: www.asms.org institutions who are not more than ORGANIZATION: Ellison Medical three years into their appointment. Foundation CONTACT: www.beckman-foundation. AWARD: Up to $100,000 per year for ORGANIZATION: The James S. Mc- ___com four years Donnell Foundation DETAILS: Ellison Medical AWARD: Up to $450,000 over three Foundation’s New Scholar Program to six years ORGANIZATION: Burroughs Wellcome in Aging funds basic biology research DETAILS: The James S. McDonnell Fund into development and age-related Foundation’s 21st Century Science AWARD: $500,000 over five years disorders. Researchers must be in the Initiative Brain Cancer Research Award DETAILS: Burroughs Wellcome’s first three years of their career after supports novel research into brain Career Awards at the Scientific their postdoctoral fellowship. cancer. Proposals from junior faculty Interface funds researchers with a PhD CONTACT: www.ellisonfoundation.org and those with neuroscience, genet- in mathematics, physics, chemistry, ics, molecular pathology, and tumor computer science, statistics, or immunology backgrounds are encour- engineering who study genomics, ORGANIZATION: Sidney Kimmel aged to apply. quantitative structural biology, or Foundation for Cancer Research CONTACT: www.jsmf.org model complex systems. The grant AWARD: $100,000 per year for two funds researchers for two years of years postdoctoral training plus three years DETAILS: The Kimmel Scholar Award ORGANIZATION: Kinship Foundation as a faculty member. supports young investigators who Searle Scholars Program CONTACT: www.bwfund.org are dedicated to cancer research. AWARD: $100,000 per year for three They must have been elected to an years assistant professorship or equivalent DETAILS: The Searle Scholars Pro- ORGANIZATION: W.M. Keck within the last three years. gram supports junior faculty pursu- Foundation CONTACT: www.kimmel.org ing independent research careers in AWARD: Up to $1,000,000 over five biochemistry, cell biology, genetics, years immunology, neuroscience, pharma- DETAILS: The Keck Foundation’s ORGANIZATION: Alliance for Cancer cology, and related areas in chemistry, Distinguished Young Scholars Gene Therapy medicine, and the biological sciences. in Medical Research Program AWARD: Up to $500,000 over three Applicants must have been appointed funds researchers focusing on the years to a tenure-track assistant professor- mechanisms of disease. The scholars DETAILS: The ACGT Young Inves- ship within the past two years. must have held a full-time, tenure- tigators Award promotes basic and CONTACT: www.searlescholars.net track appointment for at least one pre-clinical gene therapy research. year but not more than four years. Scientists should have an MD, MPH, CONTACT: www.wmkeck.org PhD, or equivalent degree and be a ORGANIZATION: Esther A. and tenure-track assistant professor within Joseph Klingenstein Fund five years of appointment to this role. AWARD: $150,000 over three years ORGANIZATION: PhRMA Foundation CONTACT: www.acgtfoundation.org DETAILS: The Fellowship Award in the AWARD: $30,000 per year for up to Neurosciences supports young inves- two years tigators who hold tenure-track faculty DETAILS: PhRMA Foundation’s ORGANIZATION: American Society positions and are engaged in basic or Research Starter Grants fund faculty for Mass Spectrometry clinical research that will lead to a bet- just beginning their careers with AWARD: $25,000 ter understanding of epilepsy. a focus on areas important to the DETAILS: The ASMS Research Award CONTACT: www.klingfund.org

52 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

FRESH FACES Looking Ahead

Next-Gen Tomorrow’s PIs We asked last year’s roster of promising scientists to tell us about the next generation of stars — grad students and scientists taking their ﬁrst steps. By Matthew Dublin

NAME: Michelle Chan NAME: Brian Gregory NAME: Vincent Plagnol AFFILIATION: The Broad Institute AFFILIATION: Salk Institute AFFILIATION: The Cambridge of the Massachusetts Institute of RECOMMENDED BY: Todd Michael Institute for Medical Research Technology and Harvard University RESEARCH: As a postdoc in Joseph RECOMMENDED BY: Matthew Hurles RECOMMENDED BY: Aviv Regev Ecker’s lab at the Salk Institute for RESEARCH: Vincent Plagnol is a RESEARCH: Michelle Chan is Biological Studies, Brian Gregory is postdoc in David Clayton’s group at currently working on her PhD in interested in taking what can be the Cambridge Institute for Medical Aviv Regev’s lab, where she is learned from RNA silencing pathways Research, where he is focusing on a focused on reconstructing the in plants and applying it to cancer broad range of statistical problems in evolution of gene regulation from chemotherapy. He hopes one day to population genetics and association comparative expression data. use small RNAs to antagonize the studies. One area of focus for Plagnol Chan has already won some effect of genes that protect cancer involves his work with the Juvenile acclaim for an algorithm she cells from being killed by chemother- Diabetes Research Foundation/ developed which identiﬁes all the apy. After his postdoc is completed, Wellcome Trust Diabetes and Inﬂam- regulatory modules from multiple Gregory is slated to take an assistant mation Laboratory, through which he species in a phylogeny and recon- professorship position at the Univer- aims to understand the genetics of structs their evolutionary history. sity of Pennsylvania. type 1 diabetes.

NAME: Don Conrad NAME: Elinor Karlsson NAME: Ilan Wapinski AFFILIATION: The Wellcome Trust AFFILIATION: Harvard FAS Center for AFFILIATION: Harvard University Sanger Institute Systems Biology RECOMMENDED BY: Aviv Regev RECOMMENDED BY: Matthew Hurles RECOMMENDED BY: Pardis Sabeti RESEARCH: Wapinski is primarily RESEARCH: Don Conrad is currently RESEARCH: In addition to being the focused on the evolutionary histories a postdoc in Matthew Hurles’ lab, first postdoc of the Sabeti lab, Elinor of genes and their transcriptional where he has already been first Karlsson is also gaining attention regulatory programs in yeasts. author on two papers in Nature for her efforts to find genes related Wapinski has already accomplished Genetics from his graduate studies. to disease susceptibility in African much in his young career, including According to Hurles, Conrad is show- populations by applying new mapping winning two “Best Poster” awards ing tremendous promise with solid methods she developed by working at ISMB in 2004 and 2005 which research projects on SNP and CNV with genomics in dogs. Karlsson’s presented SYNERGY, a novel algo- variation in the human genome. doctoral research focused on the rithm he designed to reconstruct Conrad is also very interested in genetic causes of diseases in pure- evolutionary histories of all genes developing and applying statistical bred dogs in a collaborative project in a large species group. methods for the measurement and between the bioinformatics program analysis of structural variation in at Boston University and the Broad human populations. Institute.

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 53

Class of 2007 WHERE ARE THEY NOW?

Rui Chen published several papers dealing with human female repro- ductive genetics and a genetic large A Year Later population study of Saudi Arabians. How has the Tomorrow’s PIs Dana Crawford is currently working Class of 2007 fared? Quite on reﬁning Vanderbilt University’s successfully, as it turns out. multiplexed arrhythmia genotyping A glimpse of what the scientists platforms. have been up to in the past year. By Matthew Dublin Greg Crawford has published several papers on high-resolution genome mapping and transcriptional regulators in the human genome.

Hooman Allayee published Colleen Delaney produced and several papers in 2008 dealing hosted a webcast for the Seattle with genetic risk factors for cardio- Cancer Center on cord blood trans- vascular disease. plantation and its treatment applications for autoimmune diseases in children.

Claudine Bartels published a review Laurence Etwiller co-authored a of current trends in molecular paper describing a bioinformatics diagnostics for breast cancer and method for rapid identiﬁcation leukemia. of PAX2/5/8 direct downstream targets.

Gill Bejerano received a research Lars Feuk has been awarded the Fu- grant award from the Okawa ture Research Leaders grant by the Foundation and a Young Investiga- Swedish Foundation for Strategic tor Award from the Human Frontier Research and will start his own re- Science Program. search group at Uppsala University in early 2009.

Philip Bradley is in the process of Matt Hurles and his team released starting his lab, which involves CNVtools, an R package for case- applying to his ﬁrst NIH grant, control association testing with recruiting grad students, and set- copy number variation. ting up a computing infrastructure.

Martha Bulyk recently published Amy Kiger is concentrating on a paper describing UniPROBE, an elucidating the genetic basis online database of protein binding for cell shape in Drosophila. microarray data on protein-DNA interactions.

54 WWW.GENOME-TECHNOLOGY.COM______DECEMBER 2008/JANUARY 2009

Anuj Kumar published several pa- Pardis Sabeti continues to perform pers in 2008 and completed large- with her band, Thousand Days, and scale studies of yeast ﬁlamentous parse out evidence of selection in growth which revealed hundreds of the human genome. genes previously unexplored in this cellular process.

Jun Li published research in Nature Jonathan Sebat has been devel- demonstrating that the greater the oping new approaches to gene geographic distance between a discovery in mental illnesses such population and its African ances- as schizophrenia based on analysis tors, the more changes accumulate of rare structural variants. in its genes.

Vince Magrini is now a research Sarah Trimpin is now an assistant assistant professor at Washington professor of chemistry at Wayne University’s Genome Sequencing State University. Center.

Jarrod Marto and his team are Annie Tsong is developing a working on establishing an infor- graphical model to quantify matics environment that enables conservation and systematically self-directed discovery and cus- identify changes in promoter com- tomization for mass spectrometry ponents of S. cerevisiae. data analysis.

Josh Mendell became a Leukemia Jernej Ule received the ERC Young and Lymphoma Society Scholar Investigator Grant and a Human and published work describing Frontier Science Program grant; how the Myc oncogene represses he also wrote a review article on tumor-suppressing microRNAs in RNA-binding proteins in neuro- cancer cells. degeneration.

Todd Michael is using his newly Yuntao Wu and his team completed acquired SOLiD sequencer to ﬁnd a major study identifying an mutants, SNPs, and structural vari- essential role of the HIV-1 envelope- ants; he also uses it to perform de chemokine coreceptor signaling in novo assembly of small genomes facilitating HIV-1 latent infection of and to measure gene expression. resting CD4 T cells.

Madhugiri Rao authored numerous Kun Zhang spent his ﬁrst year scientiﬁc journal articles and chap- as a junior faculty member ters; he also acted as a judge to the winning R01 grants under the State Science and Engineering Fair Human Microbiome Program in Florida. and the epigenomics initiatives.

Aviv Regev established a compu- Heng Zhu continued his research tational framework to study efforts looking at expanding protein regulatory networks. She also chip technology to various model won a Sloan Fellowship and the systems. NIH Director’s 2008 Pioneer Award to support her research.

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 55

Alan Guttmacher Alan Saltiel Thanks to National Human University of Michigan Genome Research Life Sciences Institute Today’s PIs Institute

Victor Ambros Ross Hardison Steven Salzberg University of Pennsylvania State University of Massachusetts University Maryland Medical School

Robert Austin Mary-Claire King Stuart Schreiber Princeton University University of Broad Institute Washington

Peer Bork Marcie McClure Dick Smith European Molecular Montana State Paciﬁc Northwest Biology Laboratory University National Laboratory

Charles Buck Bud Mishra Janet Thornton Purdue University New York University European Bindley Bioscience Bioinformatics Center Institute

James Collins Debbie Nickerson Doug Turner Boston University University of University of Washington Rochester

Sean Eddy Elaine Ostrander Marc Vidal Janelia Farm, National Human Dana-Farber Howard Hughes Genome Research Cancer Institute Medical Institute Institute

Evan Eichler Vijay Pande Hunt Willard University of Stanford University Duke Institute for Washington Genome Sciences and Policy

Catherine Fenselau John Rossi Rick Wilson University of City of Hope Washington University Maryland School of Medicine

Mark Gerstein Eddy Rubin Phillip Zamore Yale University Joint Genome University of Institute Massachusetts Medical School

DECEMBER 2008/JANUARY 2009 GENOME TECHNOLOGY 57

Blunt End HUMOR, WE HOPE

______

Genome Technology (ISSN 1530-7107) is published ten times a year (monthly except combined issues in Jul/Aug and Dec/Jan) by GenomeWeb LLC, 125 Maiden Lane, New York,NY 10038. Periodicals postage paid at New York,NY,and additional mailing offices. Genome Technology is sent free of charge to qualiﬁed professionals in life sciences research. Non-qualiﬁed rate is $149 per year. POSTMASTER:Send address changes to GenomeTechnology,Peck Slip Station,PO Box 998,New York,NY 10273.

58 ______WWW.GENOME-TECHNOLOGY.COM DECEMBER 2008/JANUARY 2009

______