Current Exchange - Spring 2014

[ Editorial Board ] Robert Aboukhalil Kristen Delevich Dr. Charla Lambert

CONTENTS

[ Executive Board ] Dr. Alexander Gann

Dean and Professor Watson School of Biological Sciences

Dr. David Stewart

3D Printing for Science Research

3

Y-Chromosome Forensics 5

Executive Director Cold Spring Harbor Laboratory Meetings & Courses

bioRxiv: The Biology Preprint Server 6

[ Contributors ]

Not Seeing in 3D: The Myth of Polyphemos

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Marek Kudla Maria Nattestad Kristen Delevich Dennis Eckmeier Michael Giangrasso Robert Aboukhalil Colleen Carlston

The Coral Reef Corner

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[ Images ] • • • • • • •

Creative Tools bit.ly/1comLFj Subhashish Panigrahi bit.ly/1bujeB9 Steve Cadman bit.ly/1fsgOpB Sotheby’s bit.ly/1e3QFQQ Infratec bit.ly/1aEhj2n Kamal-ol-molk bit.ly/1jZOk9D Wes Taylor bit.ly/1ed5D5u

DNA Learning Center: 25th Anniversary 12 Q&A — Dr. Paul Offit on the Vaccine/Autism Craze

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Cellular Models for Autism Spectrum Disorders 18 Q&A — Dr. Elaine Fuchs on Being a Female Scientist 20

From the Cover Page:

Current Exchange is a student-run magazine, published biannually as a joint venture between the Meetings & Courses program and the Watson School of Biological Sciences at Cold Spring Harbor Laboratory.

Current Exchange is published by 11factorial. For more information, visit our website at 11factorial.com or contact us at hello@11factorial.com.

The opinions expressed in the articles herein only reflect the opinions of their respective authors. All articles here are licensed under the Creative Commons BY 2.0 License.

Cold Spring Harbor Laboratory is a place for scientists from across the globe to meet and share their research and wisdom with colleagues. The front cover shows where the approximately 8700 scientists originated who attended a course, workshop, meeting, or special event at Cold Spring Harbor in 2013.

Circle size and color reflects the number of scientists visiting from that location; yellow, small circles indicate the smallest numbers of attendees and large, dark pink circles indicate the greatest number of attendees. The scientists came from all 50 U.S. states plus 55 other countries. In 2013, scientists visiting from locations outside the U.S. added up to more than 2700 international connections.

COVER ART BY MARIA NATTESTAD

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TECHNOLOGY

3D Printing for Science Research Marek Kudla / PhD Student, Watson School of Biological Sciences, CSHL

Buying a 3D printer started as a desire to experiment and to feel empowered by the ability to create. Ten weeks after placing the order—and following some hectic unboxing—the printer was in the lab and ready to use. We hoped it would give us the ability to design and manufacture parts that would be needed for future experiments.

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What if we could put together several useful 3D designs to make a ‘lab seed’ for starting scientists?

New faculty who are just getting started could simply manufacture what they need.

equipment, my mind fills with excitement when I think of all the creativity that went into it, a creativity that should be commonplace in the scientific environment. This goes against all current trends, however, since most of molecular biology is reduced to kit-based science, which makes it more difficult—especially for scientists in training—to understand the underlying biology. Let’s not forget that the greatest discovMost labs have equipment that was hacked eries in molecular biology happened by hacking together by clever souls. Those range from cus- something together to achieve something new; tom-made PC cards to the plate colony replica- just think of the proverbial Hershey blender. tors, made from just few pieces of common-use items. Whenever I come across custom-built What stemmed from these thoughts was the

realization that when starting up the lab, one need not necessarily buy all the equipment; rather, labs could simply print what they need. It is no longer surprising to life science researchers how expensive enzymes and other molecular biology products are. A price of $200 per 100µL of enzyme lies on the cheap side of the spectrum. What is surprising is how this pricing also extends to mundane lab necessities such as Western blot boxes, tube racks and pipette holders.

While some high prices are understandable due to the limited production run, other price in-

creases seem to come straight from the moon.

Consider the magnetic racks used for magnetic bead separation. Those are simply Eppendorf tube racks with permanent magnets fitted to them. Not exactly high tech, but this item carries the price of $500 if not more, and all for a product that is dwarfed in complexity by many a child’s toys. Although you could use a magnet if tight on budget, a more ergonomic solution is preferred for everyday work. Hence, the racks are here to stay and become a highly coveted item in laboratories with few resources.

This is where the 3D printer solution comes into play to print your own equipment. But how do you justify its purchase? Simple: Print five items and you’ve already recuperated the cost of the printer. Of course, you must still order magnets (eight pieces, $1 each) and do some simple assembly but it’s worth the trouble.

This is a great idea, but is it realistic? From our experience, we were pleasantly surprised by the performance of the printer we purchased. We would stand by the printer, watching in awe as the object emerged as per the specification of our design.

What came later, however, was an even greater surprise: the printed object’s hardness combined with its low weight. This is due to the internal structure produced by the printer, which occupies only 10% to 15% of the internal volume (and resembles a honeycomb). Interestingly, the level of the infill can be regulated to produce objects which are more solid and durable.

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Print five items and you’ve already recuperated the cost of the printer.

As for the object’s finish, while it is potentially watertight, the surface has a rough appearance as it is composed of plastic extruded from the nozzle and the machine has no way of smoothing it out. This can be rectified by rubbing some acetone or sand paper across the surface. The plastic filament is relatively cheap, with 2 lb spools priced at $50, and there is a selection of colors and properties to choose from. It is possible to print transparent or flexible objects, or even dissolvable ones for use in particularly difficult models that require support. The posWith examples like this, an idea came to mind. sibilities are endless and the modeling software What if we could put together several useful 3D can be surprisingly easy to use nowadays, with designs to make a ‘lab seed’ for starting scien- Google Sketchup being the leading example. tists? New faculty who are just getting started could simply manufacture what they need.

We are still far from push-the-button-and-forget consumer model. Although the print process A quick search in the standard repository of printable things [http://www.thingiverse.com/] produces examples of many useful objects, like electrophoretic boxes (just add platinum wire), gel combs, magnetic racks, pipette hangers and holders, ice box solutions, etc. You can even find parts for a functional tabletop spindown microcentrifuge! Although additional parts and assembly are required, you are again getting a $500 item for much less.

is automatic, you still need to process the design file even if you downloaded it. This process translates the 3D model into the series of com-

mands for the printer. Next you need to transfer the file to the printer’s SD card, level the working area and start the print. Additional calibration and filament maintenance is sometimes required, so some practice is needed to run things smoothly. There are additional problems that may manifest themselves during your printing adventures, such as the clogging of the printing head, unexpected power losses which stop your print, uneven shrinking of the plastic or sagging of overhanging parts. About half the time, we got exactly what we expected, while most of the problems were addressed by revising the design or experimental conditions. Of course, creating your own design requires more work.

In summary, the time for obtaining a 3D printer for your lab is right around the corner. It can justify its cost in a stunningly short time and with a relatively small investment of curiosity and some persistence. All labs should seriously consider getting one! ■

FORENSICS

Y-Chromosome Forensics Maria Nattestad / PhD Student, Watson School of Biological Sciences, CSHL

In 1989, a woman in the U.K. was raped at knifepoint, but the DNA of the perpetrator did not match anyone in the country’s database.

The crime went unsolved for over two decades until last year, when a new sample entered into the database matched the perpetrator’s DNA by 50%, which led police to test the DNA of the relatives of this man. His father, Barry Howell, was an exact match to the DNA left behind by the perpetrator and the evidence was used to convict him of rape.

Police investigators routinely collect DNA in violent crime cases but often fail to find a match in the databases. However, an alternative is to leverage the power of Y-chromosomes to catch more criminals.

All men have one Y-chromosome that they inherit from their fathers, who inherited them from their fathers, and so on. In most of the world, last names are also passed on from father to son, which means that knowing a man’s Y-chromosome can give a good prediction of his last name (Gymrek et al, Science, 2013).

In order to make such predictions, a database that links Y-chromosomes to last names is

needed. Such a database already exists: YSearch.org allows men to trace their ancestry by providing their own Y-chromosome data.

When DNA is left at a crime scene, police typically send the sample to a lab for a standard analysis, which means testing the same markers as in the official DNA database. Markers

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police would have to confirm which man in the family committed the crime by testing all the men at the standard markers used by the official database.

Barry Howell was caught due to the partial match between his and his son’s DNA. It is possible to catch many other criminals by finding

Knowing a man’s Y-chromosome can give a good prediction of his last name.

are specific places in the DNA where people tend to be different. The official databases store the results of testing the same markers in many individuals.

If comparing the DNA at the standard markers in the official database does not yield a match, the next step could be to test the Ychromosome and look up the results on YSearch.org or in the criminal databases. If there is a particular last name that comes up from this search, police could get a warrant and test the DNA of men with that last name. They could start with men who live close to the scene of the crime. Because fathers, sons, and brothers will have nearly identical Y-chromosomes, police would only need to test one man per family.

However, if a Y-chromosome match was found,

partial matches to more distant relatives by focusing on the Y-chromosome. Since the Ychromosome travels from father to son without mixing with maternal DNA, it may be possible to catch criminals through distant male relatives.

That said, there are several privacy issues associated with such a proposal. For one, individuals uploading their DNA information online can breach the privacy of their relatives and potentially place them under police scrutiny.

Also, requiring that all men with the same last same be tested is quite intrusive. As is common in ethics, there are tradeoffs between privacy and security ■

INTERVIEW WITH JOHN INGLIS

bioRxiv: The Biology Preprint Server Kristen Delevich / PhD Student, Watson School of Biological Sciences, CSHL

It’s customary in my lab to check the top science journals weekly to see what articles have been posted to the advanced online publication sections. It isn’t uncommon for me to arrive at lab in the morning and be greeted with, “Have you read so-and-so’s new paper?”

“No. When was it published?”

“Today.”

Point being, scientists are eager to access new scientific data as soon as it’s made available.

The latest findings motivate new research questions and fill in gaps in knowledge, helping scientists to design experiments and interpret the results of work in progress. While advance online publication makes articles available as soon as the peer review process is complete, that process can still take many months. Imagine accessing an early version of a manuscript at the same time, or even before, it’s been received by journal editors.

That’s the idea behind the new biology preprint server from Cold Spring Harbor Laboratory, bioRxiv. BioRxiv allows research scientists to upload and read (for free) manuscripts prior to peer review and publication, thus disseminating results freely and rapidly. Once a manuscript is posted to bioRxiv, it receives

a citable web address and is discoverable in web searches. Scientists can then comment on the merits and weaknesses of the manuscript on bioRxiv, potentially influencing how the final version appears. This model is based in part on Cornell University’s arXiv service, which has been a mainstay of the math and physics research communities for the past two decades.

I talked to Dr. John Inglis, Executive Director and Publisher of CSHL Press about his plans for bioRxiv.

———

What, if any, is bioRxiv’s relationship with arXiv? The first conversation about the role of a preprint server in biology took place between me and Paul Ginsparg (the founder of arXiv) about 10 years ago. My conclusion at that stage was that it would not work in biology as it was at that time.

More recently, we’ve been tracking the increase in amount of biology that’s been posted to arXiv. You can see a dramatic increase in the volume of material posted to the quantitative biology section, which is the only section they have that addresses biology.

ArXiv was aware of this trend but had no problem with our attempting to build a complementary site that had features and functions that were more familiar to people in mainstream biology. In fact, Paul Ginsparg became the first member of our advisory board. While we have no formal association with arXiv we are very similar in terms of our goals and aspirations, and hope to be talking to them as we get further along.

How do you envision the process from submission on?

A manuscript can go through a very lengthy process of review at a given journal and then the answer can be “no thanks.” In the meantime, a draft of that manuscript can be on the bioRxiv server for the benefit of the broader community who now have access to the information it contains. It has to be taken skeptically because it has not been peerreviewed, but its contents may be valuable and should be critically evaluated. Eventually one hopes that the manuscript will be adapted for the purposes of a journal, and it will find its way into the formal literature. We keep saying at every opportunity that bioRxiv is not a journal, with the quality assurance and imprimatur that journals traditionally provide. It’s a tool for the rapid distribution of research results and feedback on work in progress.

Through its conferences, courses, and publications, Cold Spring Harbor Laboratory has provided a service of communication to the scientific community for many decades, going back to 1933 and the first Symposium in Quantitative Biology.

We see bioRxiv as an extension of that: a new tool for professional communication amongst scientists, one that operates in the digital world and involves critical evaluation, skepticism, attack and defense - all the sorts of interactions that are on display at meetings here on the campus.

How will submissions be filtered to ensure that they’re scientific?

We have two levels of scrutiny. One of them being a purely clerical one to ensure that what has been submitted is not obscene or spam.

Then we have a growing community of bioRxiv

Affiliates, working scientists who have agreed to just look at submitted manuscripts without evaluating their quality and identify them as science rather than non-science or pseudoscience.

conversations with organizations that might help us with the running costs.

That’s doable at this early stage when the number of submitted manuscripts is still manageable.

We’re not aligning ourselves with any movement at all. What we’re doing is responding to growing interest and desire within the scientific community for different forms of communication that are more open, more immediate, and in many ways more unfiltered than the conventional journal system is.

We have two ways of tagging the material that’s deposited – one is to put it in a subject category, for example, “genomics”. The other one is more interesting – we’re asking authors to flag as “new results”, “confirmatory results”, and “contradictory results” to give the reader a little bit of extra insight into what the significance of the manuscript is.

That’s another part of the service we consider this server can provide. It’s difficult to get confirmatory and contradictory results published formally in journals, so this is a way of sharing that information.

How is bioRxiv being funded?

In the beginning it’s being supported by the Laboratory. You’ll see when you look at the site that it’s pretty basic; it’s not sophisticated, not slick. We haven’t spent a fortune on graphic design. It’s essentially a bunch of manuscripts formatted as PDFs, with supplementary data where appropriate but no bells, no whistles. You take it as you find it. I have held back from doing anything about outside financial support until we get up and running. Soon I’ll start a round of

Are you aligning yourself with the open access movement?

As the publisher of two of the top three genetics journals, CSHL Press is very invested in the value that journals bring to the scientific process and we’re very proud of the peer review that takes place at our journals.

There is a tendency at the moment to dismiss peer review as obstructive or harmful in some way, but I’m not willing to take that position.

Is it perfect? No, but I see a lot of people putting an enormous amount of effort into that process, and I think that’s very valuable.

I hope bioRxiv will become part of the ecosystem of scientific communication and be judged and valued for what it is, not for what it isn’t. I think journals will continue to have an important role in the filtration and validation processes they have always had.

I don’t see that bioRxiv will necessarily undermine that role, but I do think it can

assist in a variety of other ways with the rapid dissemination of results, communication of work in progress, and facilitation of community feedback, and doing all of that in an open way. That’s a little different than the concept of open access that is changing so much of how journals operate.

What do you foresee as challenges facing bioRxiv?

We want to communicate with the scientific community in its widest sense. What’s going to capture attention obviously requires scale, and scale on bioRxiv requires a culture shift within biomedical science. What would upset me most is that there is a knee-jerk negative reaction to bioRxiv that doesn’t allow it the chance to reach its full potential. Obviously we want this to be a success and will work hard to make it so, but ultimately it’s the research community that will determine that.

At this stage we don’t know all the ways that bioRxiv will function. It’s a new idea for most people in biology, and I think it’s going to be fascinating to see how the community deals with it ■ ——— BioRxiv launched on November 11, 2013 and is currently accepting submissions. You can learn more at biorxiv.org, and see a list of academic journals by preprint policy curated by bioRxiv advisory board member Dr. Leonid Krugylak at bit.ly/KYBSdk.

NEUROSCIENCE

Not Seeing in 3D: The Myth of Polyphemos Dennis Eckmeier / Postdoctoral Fellow, CSHL

In Homer’s ‘Odyssey’, the ancient Greece king Ulysses lost his way at sea. Among his many supernatural encounters was the Cyclops Polyphemos. He was a feared warrior, cannibal, and giant demigod with one important weakness: he had only one eye in the center of his forehead.

Ulysses stabbed that eye to blind Polyphemos and escaped by hiding among the Cyclops’ sheep. But there is another myth that, if true, would have affected Polyphemos severely: the myth that the one-eyed couldn’t estimate depth.

Common knowledge is that seeing ‘in 3D’ requires good sight on two eyes, or stereovision.

The mechanism is based on the two eyes being focused on one object. As each eye looks at the object from a different angle, the two images differ from each other.

Based on these differences, the brain can estimate distances. The greater the difference, the better stereovision works. This has two important consequences: stereovision works better when the object is close and when your eyes are further apart. Thus, stereovision only works within a limited range depending on how

far the two eyes are apart – just a few meters for people, centimeters in small birds.

Not every animal - or human - has two eyes that are far apart. For example, small animals like bees or even small birds are almost ‘oneeyed’ for the purpose of stereovision. Their eyes are very close to each other, allowing only very short ranges of working stereovision. Still, they are capable of virtuous flight maneuvers.

Further, one-eyed people are – when it comes to managing in every-day life - usually far less impaired than the depth perception myth is trying to sell us.

Finally, most of us seem to share the notion that the stereovision-based 3D cinema technology doesn’t really add much depth to a movie (in the literal sense, in the context of perception) – we immerge as easily into conventional, ‘twodimensional’ movies.

The question arises, what other mechanisms allow us to see the three dimensions. There are several mechanisms for monocular depth perception, or depth perception with only one eye.

All of them are based on the design of the eye itself and the consequences that arise from basic optical geometry. In this article I introduce two of them which are closely related and have an impact on our everyday life: perspective and motion parallax.

Perspective Perspective means that objects far away create a smaller image on the retina than objects that are close to you. This is because we can only see light beams that cross exactly in the

Examples of perspective: In the two figures above, objects further away seem smaller

9 iris. Thus, the single eye covers a cone-shaped space in front of it. While the eye sees a small area in close distance and a large area in far distance, the total image stays the same size.

In other words, distant objects must produce smaller images than close objects. As the angles between the contours of an object and the

playing hobbits in The Lord of the Rings movies were often simply placed further back than the other actors. By carefully ensuring that depth cues that would give their real position away were hidden, the illusion of very small people was created.

objects. This is because the close environment is represented on your retina larger than the distant environment.

A change in eye position thus leads to a large change in the position of close objects on the retina but only a small change for far objects.

Example of motion parallax: In the figure above, objects closer to us move faster across our field of vision

iris become smaller the further away it is and so does the image on the retina.

The brain is trained to take into account the effects of perspective and uses hints from a scene to estimate distances. Painters make use of this effect and include a point of focus in their realistic art. All lines that are supposed to look like they point away from the viewer, ‘into the image’, converge on this point of focus, creating the illusion of distance. It also helps the

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Motion Parallax Motion parallax is basically ‘perspective in motion’. Like in stereovision, the brain compares different images. However, the images are not acquired simultaneously but in a sequence while the observer moves around. The same principles that apply to perspective also apply here, with some very interesting effects.

The images of objects at different distances do

Common knowledge is that seeing ‘in 3D’ requires good sight on two eyes, or ‘stereovision’.

painter estimate the size an object needs to be so as to appear at the correct distance.

Some artists play with perspective to create astonishing illusions. For example, the actors

not change with the same dynamics. When you approach an object, its image looms bigger and when you move away, the image shrinks. Also, images of objects in the distance will move slower across the retina than those of close

You can observe motion parallax when looking out sideways of a moving car. You will see the objects at the side of the road, like signs, move across your field of vision much quicker than objects in the distance. Or you can hold up your finger and move your head side-to-side to see how the finger changes its relative position to the background.

Neuroscientists studying the natural behavior of animals – including myself and my collaborators at Bielefeld University in Germany during my PhD training - found that animals control their movements so that they can extract depth cues from visual motion more easily. They also make specific use of the visual motion for navigation. We can learn from these animals how to solve our own navigational problems. For example, three months ago, Ig Nobel prize laureate and neuroethologist Dr. Emily Baird and her co-authors published a general mechanism for landing aircrafts. It is based on their studies on honey bees landing on flat, vertical surfaces.

The mechanism is strictly based on the visual motion. Such a mechanism could be applied by anybody and anything that flies and lands on any surface ■

THE CORAL REEF CORNER Michael Giangrasso / PhD Student, Watson School of Biological Sciences, CSHL

Coral reefs are some of the most complex, yet poorly understood, ecosystems on Earth. Their existence appears to stem from the ocean’s desire to remind us of its formidable capacity for biological innovation.

Built by colonial cnidarians and teeming with fish and invertebrates, these underwater paradises exist in a state of constant flux.

coral reef aquarium becomes a little bit of a fanatic so today, and in future issues of Current Exchange, I will attempt to explain why. Who knows—maybe you’ll find that you’re a bit of a fanatic yourself.

What are corals?

The first and perhaps most astonishing fact about corals is that they are metazoans, or animals.

More specifically they are cnidarians, a phylum that also includes sea anemones and jellyfish.

So specialized are reef organisms to their particular ecological niche that merely a decade ago, it was nearly impossible for a person to recapitulate the delicate and awesome beauty of a reef in their own home. Today, things are different.

A dedicated community of hobbyists has generated a vast amount of information about the care and maintenance of captive reef ecosystems, thanks in no small part to the advent of the Internet.

I have been a reef enthusiast since I was 13 years old, and I grew up in online message boards such as Reef Central (reefcentral.com) and in monthly reef meetings scattered across Long Island. The truth is, everyone who keeps a

Soft corals can exist as free-living single polyps, or in colonies. This is a diverse and hardy group of corals, united in their distaste for CaCO3 secretion. Pictured: A few tiny green star polyps (Briarium) will rapidly grow into a “lawn” of colonial polyps, whereas the red mushroom polyp (Discosoma) will divide slowly to produce large individual polyps capable of relocation. A hermit crab (unidentified) examines the scene. Bonus fact: Red Discosoma corals were the source of dsRed (a form of RFP).

It is important to limit the number of fish in a reef aquarium, as they produce a lot of waste and may snack on corals or other invertebrates.

Pictured: Clownfish (Amphiprion ocellaris) are among the safest fish for a reef aquarium.

These juvenile clowns are presently male, but in time the dominant fish will grow larger and adopt different coloration as it morphs into a female.

An easy way to think of corals is to imagine them as upside-down jellyfish. A mouth, set in a central disc, is surrounded by a ring of 6 or 8 tentacles. This simple organism is a coral polyp, and the corals that most people are familiar with are actually colonies composed of many hundreds or even thousands of polyps.

Many coral colonies also secrete a calcium carbonate “skeleton,” which eventually contributes to the overall structure and substrate of the reef. Many corals have a symbiotic relationship with photosynthetic dinoflagellates called Zooxanthellae, which are the source of the many astonishing colors of corals. Zooxanthellae live inside the clear bodies of coral polyps, and produce sugars to nourish the corals in exchange for a safe place to live.

Coral bleaching, which occurs when a coral is severely stressed, occurs when Zooxanthellae “jump ship” and abandon the dying coral. Today, mass coral bleaching is occurring at an ever-accelerating

pace due to human disruption of the ocean environment. It is sobering to imagine that, one day, corals may only live on in the aquaria of reef enthusiasts.

Types of Corals Hobbyists typically describe corals as belonging to one of three groups, based on polyp morphology and the presence of a calcium carbonate skeleton.

Large polyp stony corals (LPS) also secrete a CaCO3 skeleton, but their polyps are larger and extra tissue is apparent. LPS corals can supplement their diet with food captured via their long “sweeper tentacles.”. Pictured: Red Chalice coral, Echinophyllia sp.

Small polyp stony corals (SPS) secrete calcium carbonate skeletons with intricate branching patterns, and require large amounts of light and current in order to thrive. Pictured: Montipora and Acropora species, with red Gracilaria macroalgae in background.

Small polyp stony corals (or SPS) have intricate and often branching skeletons, bright colors, and tiny polyps. They are both the most immediately recognizable corals and the most difficult to grow successfully, requiring tremendous amounts of light and current and pristine water conditions to truly thrive.

Large polyp stony corals (LPS) tend to be easier to maintain, and their large polyps with long “sweeper tentacles” are able to catch a meal to supplement their diet. Care must be exercised in positioning these corals, as their long tentacles can sting and kill nearby corals overnight.

Soft corals are by far the easiest to maintain in captivity. As their name suggests, these corals do not secrete a skeleton, and they can be found in colonies or as free-living polyps. Most reef hobbyists start out keeping soft corals, and then move on to their more finicky stony brethren ■

INTERVIEW

Dr. Paul Offit on the Vaccine/Autism Craze Robert Aboukhalil / PhD Student, Watson School of Biological Sciences, CSHL

Paul Offit is a Professor at the University of Pennsylvania and the co-inventor of the rotavirus vaccine, which protects against a disease that affects over 500,000 children every year around the world. When he visited Cold Spring Harbor Lab for a public lecture about alternative medicine, we sat together and discussed the history and recent events surrounding the vaccine/ autism craze.

Let’s start in 1998. Andrew Wakefield publishes a paper in The Lancet. What does he claim?

His paper was a case study of twelve children with neurodevelopmental delays. Of those twelve, eight had autism and all had recently received the combination of Measles, Mumps and Rubella vaccine (MMR).

Of the children with autism, he—as a gastroenterologist—believed that they also had something called lymphomodular hyperplasia, which

is to say they had an increase in the size of what are collections of lymphocytes within the intestinal wall.

And he thought these were related?

Yes. He hypothesized—without a shred of evidence to support it—that because the MMR was given in combination, it had somehow overwhelmed the immune system, allowing measles vaccine virus to replicate in the intestine, cause intestinal damage and allow for the increase of brain-damaging proteins, which would travel to the brain and cause autism.

However, there was nothing to support that.

Even more importantly, he didn’t have any control groups to show that the rate of autism was greater in vaccinated than unvaccinated children.

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The reviewers didn’t object to the lack of controls?

Four out of six reviewers thought it should have been rejected, but the editor of the journal, Richard Horton, was a friend of Andrew Wakefield, and he decided to publish it anyway.

I think he slipped from editorship into journalism.

It should have never been published.

What happened after publication?

There was a storm of media controversy. This disorder—autism—which was causing children to suffer, which was financially and emotionally crippling for parents taking care of those children, now had a cause. It now had a villain and

There were several children who died from measles as a consequence of this false, ill-conceived and unsupported paper.

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Larry King went from mother to mother and asked “What do you think causes autism?” and you’re thinking “Why don’t you have an autism expert on the show and ask them what causes autism?

that villain was the MMR vaccine.

The media in England exploded and, as a consequence, thousands of parents chose not to give their children this vaccine. There were hundreds of children who got measles; there were several children who died from measles as a consequence of this false, ill-conceived and unsupported paper.

How long did it take before it got to the US? It took years. It’s Dan Burton, who was a Republican congressman from Indiana, who held a hearing in which Wakefield spoke. That was really when it hit in the United States. There was a paper published in Pediatrics by Michael J. Smith and co-workers, and they estimated that as a consequence of the media attention to MMR’s possible cause of autism, parents of 125,000 children chose not to vaccinate with MMR. Subsequent outbreaks in the US were probably a consequence of that.

How much have the rates of Measles, Mumps and Rubella increased?

In the US, it’s not that bad. We’ve had outbreaks in 2008 and 2011; there were a couple of hundred children. But remember, before the measles vaccine, we would have several million cases of measles, 100,000 hospitalizations and 500 to 1000 deaths, so this is really just a blip.

There have been no deaths from measles in the US but this is not true in Europe, where as many as 13 died. Recently, there has been a big outbreak of measles in Swansea, Wales, and that was all a direct result of people choosing not to get the vaccine because they’re scared—more scared of the vaccine than they are of the disease.

Around 2010, the paper got retracted.

It seemed like it didn’t have much of an effect.

It’s hard to unring the bell, it’s hard to unscare people, and that’s what happened here. You know, bad science gets published all the time and rarely gets retracted. When it gets retracted, it’s because there’s been some element of

fraud, and that’s what was true here at many levels: (1) Wakefield failed to let many of his coworkers know that he had been receiving a lot of money through a personal injury lawyer to essentially launder legal claims in a medical journal; (2) Five of the eight children in that paper were in the midst of suing pharmaceutical companies and that never became clear. In the US, it would have been much more harshly treated than it was in England.

The British Medical Journal, who had pushed for that paper to be withdrawn, recently had an article that went through what was the fraudulent nature of that paper. Andrew Wakefield tried suing them for it but it’s been thrown out.

How did this affect the anti-vaccine movement?

Crazy as this may sound, the anti-vaccine movement was hurt by Andrew Wakefield because he was their bell-ringer. And not only

“

We see celebrities all the time on big screens, and they’re therefore larger than life. At some level, we think we know them. You see Jim Carrey in these roles where he’s funny, kind and affable and you think you know him so you trust him.

We make the mistake in believing that, if parents have a child with a disease, that somehow they are experts in the disease. It doesn’t. It only makes them an expert in their child. Period.

But I remember once on another Larry King show, there were three mothers of children with autism: Jenny McCarthy, Holly Robinson Pete and a non-celebrity mom. Larry King went from mother to mother and asked “What do you think causes autism?” and you’re thinking “why don’t you have an autism expert on the show and ask them what causes autism; they’re the ones researching it.

But such is national television.

Even Dr. Oz has come out and said he’s not too sure if vaccination is a good idea.

I was on his radio show once and he clearly didn’t believe what I was saying because he kept asking me the same question over and over again. He just didn’t believe my answers!

And he is certainly brilliant: he went to Harvard for his undergraduate years, attended Penn

We make the mistake in believing that, if parents have a child with a disease, that somehow they are experts in the disease. It doesn’t. It only makes them an expert in their child. Period.

was he wrong, he was fraudulently wrong—and people don’t like frauds.

Both the British press and the American press turned on Andrew Wakefield because they felt so duped by him.

Last year, I saw Larry King interview Jenny McCarthy and Jim Carrey about autism. They were considered experts on autism.

Medical School and climbed the ranks at Columbia to become a full professor in Cardiovascular Surgery. That’s not easy to do—certainly one has to largely embrace modern medicine to hold people’s hearts in their hands and fix them.

Didn’t he write a book about vaccines?

Yes, he wrote a book with Michael Roizen that had a lot of misinformation in it. When asked

by CNN’s Joy Behar whether he vaccinated his

16 children for influenza, he said no.

It’s doable.

But he’s come around actually recently. He’s retracted some of the things he said in the book.

There have been a lot of people who have suggested ways to treat autism, a lot of which was made popular by Jenny McCarthy by a book she wrote. Can you give us a few examples?

When I wrote the book Deadly Choices, I specifically commented on the things in his book that were wrong and ultimately, he changed them. I think at some level, he’s interested in getting it right.

It’s unfortunate. Here’s a man with millions

“

I actually have it in my book Do You Believe in Magic? The treatments include megavitamins, restricted diets (restricting casein and gluten), anti-fungals, chelation therapy, chiropractic

But it’s “all natural” they will say, it’s “all good”, and quite frankly, it’s all unregulated. The dietary supplement and megavitamin industry are under no obligation to prove their claims or admit their harms.

of viewers on his show, and although he gives them good advice, it’s often mixed with some awful information.

It’s the guru phenomenon. Deepak Chopra, Andrew Weil, all have this almost-spiritual gurulike thing going for them where they ask you to believe them, and they make ex-cathedrous statements that you simply should believe.

It should never be about the strength of the personality of the person who’s giving advice, it should always be about the strength of the data.

manipulations, ginger (circuma longa), magnetic/electric stimulation of the brain, hyperbaric oxygen chambers, probiotics, melatonin, shots of vitamin B12, antiviral medications, parasites, injecting children through the rectum with chroline dioxide enemas, and of course, avoiding vaccines.

But it’s “all natural” they will say, it’s “all good”, and quite frankly, it’s all unregulated. The dietary supplement and megavitamin industry are under no obligation to prove their claims or admit their harms. This has been true ever since the 1994 Dietary Supplement and Health Education Act.

They’re considered a dietary supplement and not a medication?

Yes, much of it is.

Yet casine-free diets can lead to osteoporosis, people in hyperbaric-oxygen chambers can suffer perforated eardrums, and chelation therapy can bind divalent cations like calcium which are important for electroconductivity of the heart.

In fact, people have died of heart attacks associated with chelation therapy, including a child.

All these so-called treatments take advantage of the parents’ desperate desire to make their child better, and they are perfectly willing to drain these parents’ bank accounts and hurt their children. It’s awful.

What is really the definition of alternative medicine?

You could reasonably argue there is no such thing as alternative medicine, that if a medicine works, it’s not an alternative, and if it doesn’t work, it’s not an alternative. When I was training, the term was “unconventional” medicine or “fringe” medicine.

What was the media’s contribution to the MMR controversy?

It doesn’t sound as good as ‘alternative’

They were awful. They had their devil and they ran with it, and it scared parents. They were indignant at pharmaceutical companies for hiding this “fact”. And when Wakefield was shown to be a fraud, they were similarly indignant at him for perpetrating that fraud.

The term alternative is brilliant. Reasonable alternative, alternative energy, alternative views are all good. But again, medicine is medicine.

For example, acupuncture is based on an anatomy or physiology that is built on sand. The notion that putting needles under the skin is allowing Yin and Yang to be balanced and Shi to flow and therefore making your pain better, is absurd.

The media is not about educating the public, it’s about creating excitement with the public and it’s about selling advertising.

What is the role of scientists in all of this?

Every scientist should get in the game. When you see an article that is incorrect, when you hear something on the radio or when you read something on the Internet, I think you should speak up; there’s no venue too small. I think we all assume that somebody else is doing it. We’re certainly not trained to communicate science but one can learn on the job and just take it on.

you have these drugs that can have physiological or pharmacological effects yet somehow don’t have any negatitve effect. Anything that can have a positive effect can have a negative effect, and that’s certainly true here.

Many have argued that even if alternative medicine does nothing good, what’s the harm?

It’s great marketing, isn’t it? The notion is: here

Acupuncture was developed in 2nd century BC in China, in a culture that did not allow dissection. They had no idea what the brain, spinal cord or peripheral nervous system were. They devised 12 meridians--these sort of longitudinal arcs from head to toe--because there are 12 great rivers in China. They also divided the body into 365 parts because there are 365 days in the year. So unless you believe that hu-

man anatomy is based on rivers in China, then they were making it up.

This goes back to the whole placebo idea. Is there anything wrong with placebo?

I think the placebo effect is fine. I just think you have to be careful. The question is “When does alternative medicine cross the line into quackery?”. For example, you don’t want to take a homeopathic inhaler if you have asthma. Although taking a homeopathic inhaler may allow you to improve somewhat, it’s only a drug like albuterol that will significantly improve you.

Let’s talk about vitamins. If you take megavitamins and end up taking more than your daily recommended value, is it harmful?

“

Making the Rotavirus vaccine was not easy; we partnered with Merck and it took 6 years and cost about a billion dollars because you had to prove that that vaccine was exactly what you claimed it to be.

also is necessary to kill new cancer cells, which we probably generate more frequently than we’d like to think.

Worldwide, it is probably 18 billion dollars, which is smaller than the US alternative medicine industry!

The alternative medicine realm is often portrayed as a mom & pop industry.

How small of an industry is it?

What was your contribution to the field?

It’s a 34 billion dollar industry.

There are a lot of studies that show that takeing megavitamins for a very long time can increase your risk of heart disease and cancer.

This is because you tip the antioxidation/oxidation balance too much in favor of antioxidation.

Many people have said I discourage the use of megavitamins because I’m in the “pockets of Big Pharma”. Who do they think makes these megavitamins? Elves in meadows? It is Big Pharma.

Although oxidation generates free radicals, which can damage DNA and cell membranes, it

What about the vaccine industry?

I was fortunate enough to work with a team at Children’s Hospital Philadelphia to develop the Rotavirus vaccine. We had those strains in the lab by the late 1980’s. Making the Rotavirus vaccine was not easy; we partnered with Merck and it took 6 years and cost about a billion dollars because you had to prove that that vaccine was exactly what you claimed it to be ■

An innovative, accelerated Ph.D. program for exceptional students • approximately 4 - 5 years to earn the Ph.D. • broad representation of the biological sciences • first year with course work and laboratory rotations in separate phases, completed in first 10 months • elective advanced courses throughout graduate curriculum • two-tier mentoring for each student • complete funding - stipend, tuition, research allowance and associated costs provided by the School, allowing full choice of research projects Application deadline: December 1

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For more information: gradschool@cshl.edu

18

AUTISM

Cellular Models for Autism Spectrum Disorders Colleen Carlston / PhD Student, Watson School of Biological Sciences, CSHL

The genetics complex.

of

autism

are

Despite strong evidence for heritability of Autism Spectrum Disorders (ASDs)1, in very few cases has it been possible to track down a causative gene. Around one in 100 children born in the US today will be diagnosed with an ASD, and siblings are more likely (1 in 5) to be affected 2.

In monozygotic twins (who share all their genes) the concordance is even higher (7090%) while the concordance in dizygotic twins is about the same as in siblings (both share half of their genes).

Most models of ASD predict the interaction of 3-10 genes, each conferring some susceptibility, possibly also interacting with environmental triggers, to the disorder. Some may be common genetic variants, such as a version of the ApoE gene found in 14% of the population that increases the risk of developing Alzheimer’s Disease by 10-30 fold. However, there is evidence that rare variants also contribute to ASD3. Further complicating the picture, many of the same rare variants implicated in ASD

are also found in other neurological disorders (e.g., schizophrenia, epilepsy, and intellectual disability) as well as in unaffected family members 4.

Once one suspects that a particular genetic variant might play in role in ASD how is it possible to distinguish causation from correlation? The average human genome is thought to contain ~10,000 rare variants (30-50 occur de novo, meaning they appear only in the child and not in either parent)5. Most of this variation is harmless, but some may underlie ASDs. One approach is to make mouse models that possess the same variants. However, there are several drawbacks. For one, most mouse models target just a single gene and most ASD cases

likely involve multiple genes. To make a single targeted mutation in a mouse can take years of work and is expensive, and so the effort and cost in modeling a multi-genic disorder would be untenable for most researchers. Furthermore, defining what constitutes an ASD in a non-human is controversial, and determining what is relevant to mouse social communication or repetitive actions can present a challenge.

comprise less than 20% of all ASD cases, they may shed light on common molecular pathways

Roscovitine, a drug that had previously been shown to affect calcium signaling in another cell line was able to reduce arrhythmia in TS cardiomyocytes. When the TS-iPS cells were differentiated into neurons they displayed increased dendritic retraction in response to electrical activity 8, which was remarkably also restored to normal levels by roscovitine. This drug might not only help patients’ heart arrhythmias but also could possibly treat some of the neuropathies associated with TS if administered early enough to affect the dendritic arborization of the brain.

Ideally, one could work directly with humans, but with good reason there are limits to the invasiveness of human studies. Post-mortem brain tissue is sometimes available but typically scarce. The cells in preserved brain are no longer functional and one must consider the effects of treatments and medication over the patient’s lifetime. One way to circumvent these problems is to grow your own brain tissue.

The technology of iPS (induced Pluripotent Stem) cells has allowed researchers to harvest skin cells from patients with a punch biopsy, and convert those cells into stem cells using the iPS factors SOX2, OCT3/4, KLF4, and MYC. It is then possible to use growth factors to cajole iPS cells to transform into different cell types including neurons. Voilá, now you have neurons that are genetically identical to the patient.

Of course this does not create a perfect replica of the disordered brain (brain architecture is not recapitulated in a cell culture dish, nor do the cells experience the same environment as a growing brain). However, patient-derived iPS cells could be a useful tool for studying ASD at the cellular level.

“

Timothy syndrome patients demonstrating dismorphic facial features, webbed fingers and toes, and abnormal electrocardiograms 6

involved in ASD. Furthermore, studying two individuals who both share ASD and a genetic mutation is as close as researchers can come to comparing apples to apples, whereas studying two individuals with ASD of unknown genetic origins may be comparing apples to oranges.

One genetic condition that has been used as a model for ASD is Timothy syndrome (TS). This disorder is characterized by heart arrhythmias, webbing of fingers and toes, immune defi-

Around one in 100 children born in the US today will be diagnosed with an ASD, but siblings are more likely (one in five) to be affected.

It is important to remember that ASD is a heterogeneous collection of disorders that share some common features in terms of specific impairments in social communications and repetitive behaviors but are likely to have multiple causes.

Several genetic conditions in which ASD characteristics are commonly observed (Rett syndrome, Fragile X syndrome, Tuberous Sclerosis, Angelman’s syndrome, etc.) were excluded from many ASD studies because they have a known genetic cause and thus were not considered “real” autism. Although these disorders

TS are treated for their heart arrhythmias and able to survive to adulthood. When iPS cells from TS patients were made, they were first examined to make certain they displayed the same electrical properties as TS patients (they did) and then used to make cardiomyocytes to screen for drugs to treat cardiac arrhythmias 7.

ciency, intermittent hypoglycemia, cognitive abnormalities, and, in 60-80% of cases, ASD 6.

The cause of TS is a mutation in a calcium channel that is broadly expressed throughout the body and brain called CaV1.2. CaV1.2 is important in inactivating calcium channels after an action potential, and a prolonged inward calcium current causes severe heart arrhythmias in TS patients. The finding that a mutation in a calcium channel could cause ASD was the first indication that calcium signaling during brain development might be implicated in ASD. Thanks to early detection, more children with

While it may be true that the genetic basis of most ASDs remains unknown, gradually this frontier will be charted. Concurrently, it is possible for researchers to create adult-derived stem cell lines that are faithful to patients’ genetic backgrounds.

In the case of TS patients, early detection may treat both heart arrhythmias and the postnatal developing brain. Current technology allows researchers to target specific genes in human cells so that their individual contributions to abnormalities in ASD cells can be identified9.

These iPS cell models can hasten the pace of drug discovery and might also provide systems in which to test out gene-environment interactions in ASD ■ References 1. Ronald A and Hoekstra RA (2011) Am J Med Genet B Neuropsychiatr Genet 156B: 255-74.

2. Abrahams BS and Geschwind DH (2008) Nat Rev Genet 9: 341-55.

3. Sebat J et al. (2007) Science 316: 445-9.

4. Walsh CA and Engle EC (2010) Neuron 68:245-53.

5. Lecture by DH Geschwind, Cold Spring Harbor Lab Autism workshop, Jun. 8, 2013.

6. Splawski et al. (2004) Cell 119: 19-31.

7. Yazawa et al. (2011) Nature 471: 230-4.

8. Krey et al. (2013) Nat Neurosci 16(2): 201-9.

9. Gaj et al. (3013) Trends Biotechnol S01677799(13):00087-5.

INTERVIEW

Dr. Elaine Fuchs Kristen Delevich / PhD Student, Watson School of Biological Sciences, CSHL Skin has fascinated Dr. Elaine Fuchs for nearly four decades. After studying keratins, the major building blocks of epidermal cells, in her post doc, she pioneered the use of reverse genetics to effectively break keratin proteins and uncover genes that cause human skin disorders. Using this approach, she hit on the genetic basis of a blistering skin disease called Epidermolysis bullosa simplex.

Skin stem cells possess innate genetic programs, but the type of cell that

they ultimately become - say, hair or skin - is influenced by signals that they receive from their environment.

Fuchs talks about the outside factors that shaped her own development; the opportunities passed up, risks taken, and discoveries made that led her to where she is today, an HHMI investigator and the Rebecca C. Lancefield Professor of Mammalian Cell Biology and Development at Rockefeller University.

What was your childhood like growing up in the Chicago suburbs?

I think it had a tremendous impact. There weren’t many kids in the neighborhood and my sister was four years older, so I was required to have resources that were self-supportive. My mom made me a butterfly net and I would go off in the fields and catch butterflies. She would give me all her old strainers and bowls from the kitchen and I would go out in the swamps and catch tadpoles and crayfish, and my parents would buy me very rudimentary science books.

I remember once reading about an experiment that had been done on accelerated metamorphosis using thyroid hormone so I would beg

21

my father for thyroid hormone and he would get some from Argonne National Lab (where he worked), and I would do experiments on the animals that I had accumulated in the neighborhood.

It seems like you had an early interest in biology, but in college you studied physical chemistry. What attracted you to chemistry?

You’re digging up the haphazard aspects of my life! I thought I would be a biology major; I had been appointed a James scholar at the University of Illinois which was for a certain percentage of students who had done well in high school, and I’m probably the only person who’s ever turned down a James Scholarship.

It wasn’t monetary, but it was an honorary title and allowed you to take accelerated courses.

And my father said, “Why don’t you wait and

“

National Labs. And she was very strongly feminist, always supportive of women. When the National Organization for Women formed, she and her husband would march in the streets.

My sister and I were the beneficiaries of her strong feminist attitudes.

How did you relate to feminism as you went through your career?

It really wasn’t until I was on the faculty at the University of Chicago. My aunt would come into Chicago regularly, and I remember one time we were out to dinner and I had been at the University maybe two or three years and she asked me if I had ever felt discriminated against in going through my career. And I said, “No, not at all.” And she said, “Oh that’s strange, your sister has.”

And it never occurred to me. I did know that my sister had not gotten into the University

My mom made me a butterfly net, and I would go off in the fields and catch butterflies. She would give me all of her old strainers and bowls from the kitchen and I would go out in the swamps and catch tadpoles and crayfish, and my parents would buy me very rudimentary science books.

see how you do.” I don’t think my father really thought I was going to do very well in school.

And so I turned it down.

When I looked at the biology programs they had biology either for honors students or for teachers, and I thought, “Well I don’t want to be a teacher.”

When I looked at the chemistry program you could just be a chemistry major, so I just selected to be a chemistry major. And so before I ever got to do biology I realized that I really liked chemistry, math, and physics. I never got around to doing biology during the time that I was an undergraduate.

I read that your aunt encouraged you to go into medicine.

My aunt was definitely supportive. She wanted to go to medical school but was turned down.

Later on, she worked as a technician at Argonne

of Michigan graduate school because they had told her that they didn’t like to accept women they thought would get pregnant and quit school, and so she ended up going to MIT. There were aspects that I was cognizant of that were blatant, but then the more I started to think about it I thought about it the more I started to realize that my advisor from graduate school didn’t think women belonged in science, and the last advice he gave me before leaving is that if I got married and there were two jobs available in different cities that he hoped that I’d go to the one that my husband was going to.

What kept you from taking these things personally?

I think it was because I always felt that I needed to work harder. I just took them as pieces of advice that I didn’t have any reason to question or think weren’t rooted in genuine advice for me. I

just thought this was the assessment of my advisor and that I should work harder.

When in your career did you really feel passionate about what you did?

When I was at MIT as a post doc I began to really love what I was doing. Howard Green, my post doc advisor, wanted me to look at protein assembly, and I thought I really want to isolate messenger RNAs and look at gene expression using other approaches. So he let me do that without paying any attention to me, and that was very helpful. For the first time, nobody was telling me what to do, and it was do or die.

It really wasn’t until that point that I realized I had to be resourceful. Nothing was available; there were no biotech companies at the time so you had to do everything on your own, but the resources were available. For me working with the cell biologists and deciding that I wanted to do more molecular experiments, when all of these great labs were around me, taught me the value of interacting with a lot of other people. It was really that MIT experience that gave me that breadth of ability to be resourceful and interact with other people that I think has carried me along the way.

Tell us about your move to transgenic mice We had really gotten to the point where we had identified critical residues that were necessary for the filament assembly process. We were doing filament assembly in test tubes and getting defects by putting mutant genes into cultured cells and looking at how that affected in a dominant negative fashion the overall cytoskeletal architecture. We really got to the point where these were the major proteins that were expressed by skin.

The globin genes were the major genes that were expressed by erythrocytes and at that point, it was known that sickle cell anemia and thalassemia were due to mutations in globin.

So that was the point where it seemed to me that there ought to be patients walking around with keratin mutations and we had these mutations that disrupted filament assembly but looking in a petri dish at a disrupted cytoskeletal architecture didn’t give us a clue as to what human disease we should be looking at.

Irwin Freedberg, probably the most famous dermatologist at the time, (the chair of the NYU Dermatology) later told me that he had a list of fifty potential human skin disorders that were likely disorders of keratin and Epidermolysis bullosa simplex wasn’t on the list. So it

22

wasn’t obvious what human disease to look for.

And again, naively talking to my students and post docs, I thought that if there are patients walking around with these diseases, and the mutations are acting in a dominant negative fashion, if we put these genes into mice using transgenic technology we would maybe end up having mice tell us what we should be looking for.

I think one has to somewhat develop that fearlessness. Everything has been a gift; to be paid to work in a laboratory and be surrounded by students and post docs that are smart and to be able to ask these questions - it’s such a gift.

Maybe one day the funding will run out, or I’ll have to do something else, but if I have to go paint or draw or do something else, I’ll figure that out when I have to.

It was probably naïve at the time, I was not a member of HHMI when I made the commitment to do transgenics. I was hoping that maybe 10 mice would be about all I needed, and I had no clue how expensive mouse work was.

I guess I’ve always felt that way; I never really thought about a job at the University of Chicago. I thought of finding a small school with a few smart people and some students, and then this would be great. Maybe it’s that short-term sort of sense… I’ve always been comfortable with that. I guess I’m still comfortable with the notion that if I have to do something different someday, I have plenty of things I want to do

Was funding ever a crisis in your lab?

It would have very quickly been one, but I was appointed to HHMI in 1988, and at that point I had the resources needed to support my pie-in -the-sky ideas. Hughes is more or less the same kind of challenge that I really enjoy, “You’re successful, here’s the money, now go do something that is different from what you would probably do, different from what other people are doing and come come back and see us in five years.”

So you’re constantly being challenged, and I’ve always enjoyed that kind of challenge.

I encourage people to think broadly about the approaches to take to solve a problem. You have a question in science and you want to come up with the best way of getting there.

Not, “These are the skills I know, now what questions can I ask?”

Do you think the current funding situation has hampered this type of risktaking?

Safety is a natural instinct, I think. The natural instinct is “here are the skills I know how to do, and I’m really good at those skills, so I’ll just keep on doing them.” And it’s much less comfortable to take the strategy of saying “these are the skills I know how to do, but I’d really like to do this; I’d really like to know the answer to this question.”

On taking the “next step” For me it took a long time to develop the ability to think through what it is that I wanted to do because I was going in so many different directions and somehow managed to work out. In retrospect, that was a gift because I had gone through really quite dramatic changes in my approach and in my career. When I realized “I can do this”, that gave me the confidence to say, “I don’t know if I can do the next step, but I know I want to try.”

“

excited about coming in to the lab everyday to do my experiments?”

And sometimes the answer to that is just not to put blinders on. Some people can completely burn out by doing that or be very unhappy and that’s going to affect how well they do their experiments and how well they think. For me, it’s been traveling, opera, ballet, whatever; but it’s always the need to do something.

If I hadn’t have spent so much time rationalizing when the right time to have children was and then crafting a life for ten years without children and then one day realizing that my life was completely incompatible with having children.

My husband and I spent about a month talking about well now is a good time to have kids, and

Think broadly about the approaches to take to solve a problem. You have a question in science and you want to come up with the best way of getting there. Not, “These are the skills I know, now what questions can I ask?”.

with my life.

I pick the science, but if I had to tomorrow do something else, I could do it. I tell people not to worry so much about funding, not to worry so much about “What if it’s not going to work out?” That’s what I tell people in my group, worry about what you’re going to do if you do what you like doing. Just let it play itself out.

Do you feel pressure as a female role model in science to explain your personal life?

I think it is helpful just so that there has been this misperception that if a woman is going to go into science and really take a route of really doing the top state-of- the-art science that she can’t have children, it’s just too much for her to do.

A close friend of mine, Susan Lindquist, is an example that shows this conception is completely false. I make a point of saying that I believe just the opposite. It’s important to stand back from your science from time to time, and it’s also important to decide personally, “What’s going to make me happy? What’s going to make me

we just looked at each other after that and said there’s no way we wanted to do that. I thought at the time that maybe I’d regret it when I’m older, but so far I’ve never had any regrets.

Looking back on positional cloning Positional cloning… It’s hard to say whether we would take the approach we had taken. It’s a lot simpler now but it doesn’t inform you about physiological relevance, whereas the approach we took allowed us to understand the biology of what was going on, we just didn’t know which genetic disease we should be applying that to. But as soon as we did, we understood the whole biology of the system. Even if you say, “Well it’s easy to do positional cloning”, what’s the protein doing? And that’s the challenge that I find exciting.

You have to say what drives you. For me being trained as a biochemist I wanted to know how things work, how does this happen? I love the icing on the cake with the relationship to genetic disease, but I guess I’m a hardcore basic scientist, and I always will be ■

Sunrise over Lanka Pagoda - the pagoda has overlooked the Stone Lake Scenic Area southwest of Suzhou's old town for more than fourteen centuries.

Cold Spring Harbor Laboratory 2014 Meetings & Courses Meetings

Courses

Avian Model Systems

Workshop on Schizophrenia & Related Disorders

March 5 - 8 / January 3

June 4 - 10

Systems Biology: Global Regulation of Gene Expression

Advanced Bacterial Genetics

March 18 - 22 / January 10

June 4 - 24

PTEN Pathways & Targets

Ion Channels & Synaptic Transmission

March 25 - 28 / January 17

June 4 - 24

Neuronal Circuits

Mouse Development, Stem Cells & Cancer

April 2 - 5 / January 24

June 4 - 24

The PARP Family & Friends: Gene Regulation & Beyond

Genetics of Complex Human Diseases

April 9 - 12 / January 31

June 12 - 18

Meeting dates / abstracts due

Course dates

Gene Expression & Signaling in the Immune System

Statistical Methods for Functional Genomics

April 22 - 26 / February 7

June 18 - July 1

Molecular Chaperones & Stress Responses

Frontiers & Techniques in Plant Science

April 29 - May 3 / February 14

June 27 - July 17

The Biology of Genomes

Drosophila Neurobiology: Genes, Circuits & Behavior

May 6 - 10 / February 21

June 29 - July 17

The Cell Cycle

Advanced Techniques in Molecular Neuroscience

May 13 - 17 / February 28

July 1 - 17

Retroviruses

Single Cell Analysis

May 19 - 24 / March 7

July 2 - 15

79th CSHL Symposium: Cognition

Computational Neuroscience: Vision

May 28 - June 2 / March 14

July 11 - 24

Glia in Health & Disease

Proteomics

July 17 - 21 / May 2

July 15 - 28

Mechanisms & Models of Cancer

Computational Cell Biology: Mechanistic Modeling for Experimentalists

August 12 - 16 / May 30

Nuclear Organization & Function August 19 - 23 / June 6

Regulatory & Non-Coding RNAs August 26 - 30 / June 13

Translational Control September 2 - 6 / June 20

Epigenetics & Chromatin September 9 - 13 / June 27

Axon Guidance, Synapse Formation & Regeneration September 16 - 20 / July 11

Plasmids: History & Biology September 21 – 23

Molecular Genetics of Aging September 29 - October 3 / July 18

Germ Cells October 7 - 11 / July 25

Nuclear Receptors & Disease October 28 - November 1 / August 15

Biological Data Science November 5 - 8 / August 22

Personal Genomes: Discovery, Treatment & Outcomes November 12 - 15 / August 29

Stem Cell Engineering & Cell-Based Therapies November 19 - 22 / September 5

Neurodegenerative Diseases

July 22 - August 11

Eukaryotic Gene Expression July 22 - August 11

Yeast Genetics & Genomics July 22 - August 11

Imaging Structure & Function in the Nervous System July 23 - August 12

Genetics & Neurobiology of Language July 28 - August 3

Synthetic Biology July 29 - August 11

Brain Tumors August 6 - 12

Programming for Biology October 13 - 28

X-Ray Methods in Structural Biology October 13 - 28

Computational & Comparative Genomics October 29 - November 4

Antibody Engineering & Phage Display November 5 - 18

Advanced Sequencing Technologies & Applications November 11 - 23

The Genome Access Course March 31 - April 2 and November 12 - 14

December 3 - 6 / September 19

Blood Brain Barrier December 10 - 13 / September 26

www.cshl.edu/meetings CSHL course on an evening sail.

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