My Life with Verne

The author met Verne Caviness in 1972 at Harvard Medical School, Boston, MA when he was a graduate student and Verne was a Fellow in Neurology. They came to know each other well and eventually started a long and successful collaboration. This is a story about Verne and some of our colleagues over a period of about 40 years.

I first met Verne Caviness in the fall of 1972 at Harvard Medical School, Boston, MA, USA.I was a second-year graduate student working with Pasko Rakic; Verne was a fellow in neurology working with Richard Sidman.We were all part of the department of neuropathology.The department had just moved into the Boston Children's Hospital research building (now known as the Ender's building), and Verne and I were to share an office.
Verne spent most of his days in the clinic at the Massachusetts General Hospital (MGH) and came to his research office only in the evenings and weekends.We interacted only a little.However, I remember distinctly a long discussion with him about the limited path length of the beta particles emitted by tritium in histological sections.Verne, along with David Barkley [1], had just published a paper on this topic.This discussion was my first exposure to Verne's incredible intellect and was critical for my development as a scientist because it reinforced my tendency to think quantitatively about the physical limitations of the methods that we use, and, as it turns out, this was important for me a few years later when I published a paper on a related topic [2].Verne was working mostly on the reeler mouse, and, of course, we discussed his reeler work and its implications in our shared office, in larger gatherings in the department, and in a graduate course on developmental neuroscience in which Verne lectured.Verne's early reeler publications made a big splash in the literature and huge impression on me [1,[3][4][5][6].These papers documented the remarkable phenotype of the reeler mouse with an "inverted cortex" and a preservation of the birth order of neuronsacross neo-, paleo-, and archi-cortical structures.I read these papers closely as I worked on my own papers that came from my dissertation work [7][8][9].
Our office sharing came to an end when Verne moved to his own laboratory on the campus of the old Fernald School in Belmont, MA, USA.Verne's laboratory was in the basement of the southard unit which was a small cottage at the rear of the campus.The Fernald School at the time still housed some residents who could be seen walking around on the campus occasionally.About this time, the E.K. Shriver Center was built at the front of the campus along Trapelo Road.The research activities were an extension of the research at MGH, and the residents were also seen and evaluated by MGH neurologists.My wife Nancy Hayes took a position as Verne's laboratory technician, so I continued to interact with Verne and his scientific colleagues as I visited the southard unit frequently and became part of Verne's extended laboratory family.He continued to publish on the reeler mouse, but Verne was eclectic, so he also published on human brain development and developmental pathology.He shared his interest and excitement with me and others.His style as a scholar was inspiring.For example, as he worked on his paper on the cytoarchitecture of the reeler neocortex [10], he poured over the works of Brodmann [11] and other German cytoarchitectonists.His excitement was contagious, and the example he set has helped me as I have tried to follow in his footsteps.The laboratory family at the southard unit included graduate students from MIT (Doug Frost and Marshall DeVor), neurologists from MGH, and several visiting scientists.Some worked on the reeler mouse and others on human developmental neuroscience issues.It did not seem to matter to Verne what his visitors were working on; he shared the interests with everyone and we all became friends and scientific confidants.This was a very productive period for Verne, and he spent many hours in the southard unitusually in the early mornings and late evenings, as he continued to spend many hours in the clinics at MGH.
In 1976, I left Harvard with my PhD in hand.I went off to do postdocs at Duke and in Germany and eventually to become a faculty member at the Robert Wood Johnson Medical School in New Jersey (NJ).Verne continued at the southard unit, eventually becoming the scientific director of the Shriver Center and later in 1988 moving to the new Charlestown campus of the MGH.Verne and I continue to meet at the Society for Neuroscience (SFN) meetings and to discuss projects of mutual interest.What was exciting about these dinners and lunches with Verne was that he would always bring his latest colleagues with him and eagerly introduce them to me to discuss whatever it was that they were working on.It was a fabulous set of scientists that Verne had gathered around him at MGH and that he would bring to the SFN meetings for amazing discussions.It was great being Verne's friend and colleague.

The Collaboration Years
That changed, however, in the late 1980s.The change was that we became collaborators.I had lunch with Verne at the SFN meeting soon after I published the papers [12,13] that established the use of bromodeoxyuridine immunohistochemistry as a replacement for tritiated thymidine autoradiography.As I explained to him how this new method changed a 30-day exposure time needed to make an autoradiogram to a few hour immunohistochemical experiment, his eyes lit up.Then, I explained how using this method for the study of the cell cycle [14] would make these experiments possible in <5% of the time needed with tritiated thymidine, he gasped.He proposed that we combine forces and start to collaborate.Verne had just recruited a new postdoc and was raring to go.When I returned to NJ, I sent him my just-funded grant applications and that cinched the deal.A few weeks later, he came to NJ, and we rewrote his latest grant application in 3 days.A few weeks later, he invited me to MGH to give a seminar, to meet his colleagues Jean-Paul Misson, Margaretha Jacobson, and Takao Takahashi, and to teach the new bromodeoxyuridine technique.Takao was the new postdoc.Over the next 15 years, the three of us published 27 papers together (many cited elsewhere in this paper), almost all focused on cell proliferation and migration in the developing neocortex of the mouse.
The collaboration was both time-and intellectconsuming!I would go to Boston from NJ every few months.Takao would come to NJ most years, and we all spent many hours on the phone.Visiting Verne was a lesson in how to be productive.I would arrive early (on the first plane from Newark) and take the train from Logan to MGH.Verne was always already in his office (he was by this time the chair of Pediatric Neurology), where he was usually busy with a colleague or a resident.I would stay at his house in Charlestown or Rockport on Boston's North Shore.We would stay up late and then go to MGH early arriving at 4:00 a.m. or so.My only surprise with this schedule was that when we pulled into the parking garage there were already two rows filled with the cars of the surgeons who started their day even earlier!
We each had our own strengths and assignments for each manuscript.Our skill sets and our interactions were remarkably synergistic.For our first papers [15,16], Takao collected most of the data and he came up with the system of dividing the proliferative zone up into 10 μm-wide bins.I, in turn, took the data and crunched the numbers with Excel and used SAS to make 3D graphs.Verne took charge of creating the first draft of the manuscript.We used this system for all of our early data papers.Since this collaboration started just as email was becoming common and available, we learned that we could exchange drafts quickly, so we developed our own revision management system for manuscripts.One of us would take charge of the manuscript draft and control the file naming.Each manuscript had its own short name, e.g., PVE, or CellCycle; most of the time the manuscripts had pretty plain and boring names, but sometimes we would get cuteone paper [17] was known to us as "Twin_Peaks" (after the popular network TV program of that era) because the migrating cells formed a bimodal distribution in the intermediate zone after they left the proliferative population and made their way to the cortical plate.Of course, we numbered the drafts and quite early in the process, we got smart and numbered them 1, 2, etc.Only the controlling author could increase the number.As editing collaborators, we would add our initials after the draft number.This meant that all of our drafts would appear in our directories in chronological order with names that all three of us understood.We almost always had 20 to 40 drafts of a manuscript before we submitted it (fortunately, we never exceeded 99!).Our naming system let us go back and recover some valuable thoughts that got eliminated by over-exuberant editing.This saved our butts numerous times!Writing with Verne was an adventure and a lesson in the versatility of English.Verne had and used a tremendous vocabulary.To him, each word was magic and had a specific meaning.We often debated semantics and significance and would change vocabulary halfway through a manuscript.Verne also had the ability to write a vast amount quickly and to rewrite it equally quickly.I do not think he even knew the meaning of writer's block.Frequently, we would discuss a manuscript on 1 day and the next day a significant revision of that manuscript would land in our mailboxes waiting for our input.Of course, this usually happened over the weekend, as Verne had significant clinical duties during the week.This meant that large blocks of time had to be devoted to working with Verne, to discussing with Verne, and edit-ing with Verne.This was usually done live over the telephone with each of us sitting at our computers and looking at the same version of the manuscript.These sessions would last for hourssometimes with breaks where we would work individually, but always productively.In my house, these numerous and lengthy sessions with Verne resulted in Verne's name became a verb.If I was delayed or occupied, I was being "verned."If I knew that we had a weekend marathon writing session, I warned that I was going to be "verned."Being "verned" was a good thing and I miss it!
The corpus of literature that Verne, Takao, and I published over a 15-year long period tells the story of the development of the neocortex, as illustrated by our ability to quantify cell proliferation and the cell cycle in the mouse.We used the raw data to determine that the cell cycle in the developing mouse neocortex started at about 8 h at embryonic day 10 (E10) and lengthened to about 18 h at E16.This means that it takes 11 cell cycles to make the neurons that comprise the neocortex [16,18,19].We showed that at every pass through the cell cycle, an increasing proportion of the daughter cells that were generated left (or quit) the cell cycle to migrate and to become young neurons in the cortical plate [20].We then assembled the cell cycle and leaving (Q) fraction information into a quantitative model that describes the growth of the mouse neocortex across its medial to lateral extent and its total expansion during the proliferative period [21].We also generalized our mathematical model to fit the known data from rat, cat, monkey, and human, which seem to have 14, 18, 28, and 35 cell cycles, respectively, but approximately the same leaving fraction curve [22].We showed how neurons produced during a single 2-h window are distributed in the cortex [23].We proposed novel ways that the cell cycle lengthening could be used by the developing young neurons of the neocortex to specify the laminar position of cells and the differences in cytoarchitecture in the plane parallel to the ventricles [24], we explored the role of histogenetic cell death in neocortical development [25], and we contributed to the understanding of the molecular controls on the cell proliferation and cell fate processes [26][27][28][29].We did not stop there; we used our insights further to tackle human developmental neuropathology conditions, such as microcephaly and lissencephaly [30].
During the years of collaboration, Verne, Takao, and I also met for working lunches or dinners at the SFN meetings, and Verne would bring his extended laboratory family with him for general discussion.Between these sessions at SFN and my visits to MGH, I came to know many of Verne's residents and colleagues, many of whom are the people whose papers are included in this special issue (see, for example, Fig. 1).During my visits to MGH, Verne included me in everything, including, on occasion, meeting with him and his residents.Watching Verne work with his residents was witnessing a master teacher in action.He knew how to bring them to the right conclusions, and they knew how to inform him what the issues were.I am not a clinician, and I enjoyed these sessions tremendously.I use the clinical reasoning that I saw firsthand when I teach medical students.
It is hard for me to put into words the value that Verne's friendship and mentorship had on me personally and on my career; simply knowing Verne was an honor.Working with him was an honor beyond measure.As this special issue attests, his influence on the profession was deep.During the many years that I served on NIH study sections, many of my fellow study section members were neurologists or pediatric neurologists.Many of them were colleagues, former colleagues, students, or former students of Verne and had understood immediately what it was like to work with him closely.I know that my life and my career would not be what they are today if my young graduate student self had not been "verned" in our shared office over 50 years ago.

Fig. 1 .
Fig. 1.This photo was taken in 1999 in the developmental neurobiology laboratory, MGH Neuroscience Center, Charlestown, MA, USA.The people in the photo are from left to right: Sahoko Miyama, Pradeep Bhide, Richard Nowakowski (the author), Verne Caviness, Takao Takahashi, Ivana Delalle, and Tomohide Goto (photograph courtesy of Pradeep Bhide).