This article appeared in the Spring 2014 issue of Current Exchange Magazine.

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 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.

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 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.

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 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.

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 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.

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 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.

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 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.

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.

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?”

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.”

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.”

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.

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 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.

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 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 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.

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.

At this moment, millions of toilets are flushing. Whirling down the drains is something that might one day be used to treat Parkinson’s disease and ALS – urine. That is, the cells in urine. It turns out that living cells found in human urine can be programmed to generate a steady stream of brain cells. Researchers at Guangzhou Institute in China found a quick and relatively efficient method that converts urine cells into a parental cell type that gives birth to a variety of nerve cells. The hope is that that one day, a patient could submit a simple urine sample and get back the neurons he or she has lost to neurodegenerative disease.

It might be surprising that urine contains living cells in the first place. They come from the kidneys, where they line the tubules, until they detach, get excreted and become so-called urine cells. The key to transforming these simple epithelial cells into bona fide neurons is to turn back their developmental clocks. Through a process called reprogramming, scientists push adult cells to revert to an earlier, less specialized form. This process essentially takes cells through the plotline of The Curious Case of Benjamin Button. Their fixed identities unravel until a small fraction of cells ultimately resemble what they were in their infancy: embryonic stem cells.

Embryonic stem cells have limitless potential for self-renewal and can give rise to any cell type. Similarly, we begin life with myriad possibilities of who we will become, but as we go through life we make decisions that set us on a more defined path. The same goes for cells as they develop: embryonic stem cells commit to lineages that give rise to mature cell types, and normally after fate decisions are made, there’s no going back.

This made the breakthrough discovery of reprogramming factors by 2012 Noble Prize winner Shinya Yamanaka so surprising. He found that merely four gene products, called transcription factors, were sufficient to turn back the clock and reprogram mature cells to stem cells. Transcription factors are proteins that bind DNA and recruit machinery that transcribes the DNA code into mRNA that then serves as the template for protein production. The idea is that Yamanaka factors must turn on gene products that give stem cells their unique abilities. Only recently scientists have begun to carry out detailed molecular studies that track how cells change during reprogramming. It appears that cells go through distinct intermediate steps, so that like the Benjamin Button story, reprogramming really does look like development in reverse.

Reprogramming efficiency is very low in general: only a tiny fraction of the cells end up resembling embryonic stem cells. These fully reprogrammed cells are called induced pluripotent stem cells, or iPSCs. Apart from the amniotic sac and placenta (only made by embryonic stem cells) they can become any type of cell in the body – from the bone cells that form your elbow to the nerve cells that respond when you whack it. Reprogramming adult cells – be it from a cheek swab or a urine sample – into iPSCs skirts the ethical issue of harvesting stem cells from human embryos. In addition, they don’t cause immune rejection like embryonic stem cells do, because they come from the patient’s own tissue. What makes urine cells a great cell source for reprogramming experiments is that it’s plentiful and easy to collect. More commonly used cell sources require invasive procedures such as skin biopsies and blood draws. The Chinese researchers were studying methods to increase the efficiency of reprogramming when they made a surprising observation.

The gee whiz moment came when Wang and colleagues noticed that urine cells grown in a specially-defined media clumped together in a flower-like shape. This rosette pattern was reminiscent of the way that neuronal progenitors, the parental cell type that gives rise to all types of nerve cells, grow. They had stumbled on a shortcut for producing brain cells: the cells picked from the rosette expressed genetic markers that were characteristic of neuronal progenitors, not iPSCs. The urine cells acquired the ability to grow and self renew without ever becoming iPSCs. By repeating the same steps, the scientists made the same progenitor cells from three men. While reprogramming efficiency was only a fraction of a percent (.2%) they could produce enough progenitors to generate many types of mature cells found in the brain.

Besides being faster, this shortcut method is also safer than previous methods used to make brain cells. Before, scientists made brain cells by forcing mouse connective tissue cells to make proteins and RNAs normally found in neurons. This method required that viruses insert foreign DNA into the mouse cell’s genome. Unfortunately, viral integration can lead to the unwanted side effects of genomic instability and cancer. Instead, Wang and colleagues introduced a small circular piece of bacterial DNA that served as a platform for reprogramming factor delivery. Bacterial platforms multiply in the cytoplasm, and reprogramming factor expression is driven directly off of them, no integration into the host cell’s genome required.

It’s all well that urine cells could produce brain cells in a dish, but in order for replacement therapy to work, they would have to convert and survive in a living brain. To test this, researchers transplanted neuronal progenitors made from human urine into the brains of newborn mice. They saw that the urine-made neuronal progenitors produced mature brain cells that survived for at least a month in the mice brains. Follow up studies are needed to test if these neurons actually participate in brain function. Importantly, there was no evidence of tumor formation, indicating that the virus-free system could be safe for therapeutic applications.

Overall, the ability to convert excreted urine cells directly into brain cells is faster and safer than older methods that first require reprogramming to iPSCs. The higher efficiency of reprogramming mature cells directly to neuronal progenitors plus the abundance of source material, make pee-made brain cells an exciting tool for the study and treatment of nervous system disorders

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.

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.

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 peer-reviewed, 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.

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

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.

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

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. 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.

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.