B*M
2 楼
大圆满法网
为修持成佛要发殊胜菩提心！
为度化一切父母众生要发誓修持成佛！
为早日圆成佛道要精进认真闻思修行！
想解脱成佛首先要发菩提心，发菩提心首先要发慈悲心。发慈悲心就是从内心里下
决心做决定：我一定要给予一切众生安乐、我一定要拔除一切众生痛苦！当这两种想法
特别强烈的时候才能发出来菩提心。之前都是在表面上、在形式上发的，实际上并没有
发出真正的菩提心。
我们知道，一切众生都当过自己的父母，都对我们有恩德。如果不报答这个恩德，
以后还要继续互相伤害、互相结怨。只有报答他们的恩德了，我们才可以解脱，才可以
成佛，才可以不再互相讨债还债了。我们特别地想报答这个恩德，然后从内心里下决心
做决定：我一定要给予一切众生安乐，这叫慈心；我一定要拔除一切众生的痛苦，这叫
悲心。这两者合在一起叫慈悲心。
那么怎样才能给予一切众生安乐？怎样才能拔除一切众生痛苦？那个时候，为了救
度一切众生发誓发愿要成佛的念头自然而然就有了，这叫发菩提心。所以在慈悲心的基
础上才能有真正的菩提心。
菩提心有很多种，分类如下：
（1）从心力分
从心力的角度来讲，菩提心可以分为像国王一样的发心、像舟子一样的发心和像牧
童一样的发心三种。心力就是心的力量，有的人心力大，有的人心力小。
像国王一样的发心。国王的想法是首先自己登上王位，然后再维护手下的臣民。这
种发心是自己先获得佛果，然后再救度众生，这叫广大意乐之发心，也被称为如国王式
发心，这种发心的心力属于下等。
像舟子一样的发心。舟子就是船夫。意思是自己和船上的游客一起，同时达到彼岸
。这种发心是自己和一切众生同时成佛，同时到达解脱的彼岸，超出轮回，获得正果。
这叫如舟子一样的殊胜智慧的发心。这种发心的心力属于中等。
像牧童一样的发心。牧童把牦牛赶在前面，自己在后面保护牦牛，让牦牛先到目的
地，然后自己再到。这种发心是自己不成佛，先将一切众生安置于佛果，然后自己再成
佛。这是最高、最殊胜，无与伦比的发心。这种发心的心力特别大，属于上等。就像地
藏王菩萨发的愿：“地狱不空，誓不成佛！”就是这种发心。
（2）从地道界限分
依照地道的界限来分，它可以分四种发心：胜解行发心、清净意乐发心、异熟发心
和断证发心。胜解行发心是资粮道、加行道的发心。一地菩萨到七地菩萨的发心是清净
意乐之发心。八地菩萨、九地菩萨、十地菩萨的发心是异熟之发心。佛断证圆满了，叫
断证发心。
（3）从发心本体分
从发心本体的角度来分，可以分两种，一个是世俗菩提心；另一个是胜义菩提心。
世俗菩提心是登地菩萨以下的发心；胜义菩提心是登地菩萨以上的发心。世俗菩提心可
以分两个：一个是愿菩提心；一个是行菩提心。愿菩提心和行菩提心都特别重要。
对于初学者来说世俗菩提心特别重要，尤其是愿菩提心特别重要。我们天天在讲法
、闻法前念的：“为度化一切父母众生要发誓修持成佛”，这是愿菩提心；“为早日圆
成佛道要精进认真闻思修行”，这是行菩提心。这两个都是菩提心，一个是为果而发誓
，一个是为因而发誓。
我们一定要反复地这样发愿，反复地这样发誓。直到有一天，我们的相续中自然而
然就有那么个念头、有那么个想法的时候，我们才算发出来菩提心。发出菩提心以后就
好了，那个时候修行一点也不难了，因为心到位了，一切都到位了。没有发心之前无论
修什么法、念什么佛都不会有真正的收获、不会有真正的成就，因为心没有到位。心不
到位，做什么事、修什么法都不到位。
我们要发菩提心，多多地发。有一天在我们的相续中有这个愿、有这个心了，就没
有这个“我”了，就只有菩提心了。然后我们的所作所为都是善事、都是为众生、都是
消业积福。行住坐卧都是修行的过程，吃喝玩乐都是修持的方法，每时每刻都能增加我
们的智慧与福报。因为现在有我执我爱，所以我们的所作所为都是为自己、都是烦恼分
别、都是执着、都是造业。
业障深重，不怕！当我们的相续中真正能够产生菩提心的时候，无论多重的业障都
会立即消失，无论多薄的福报都会立即增长。
我们念佛、持咒、诵经、求往生，因为没有发菩提心，所以无论念诵多少遍都没有
用，解脱不了！在发出菩提心的基础上，才能往生西方极乐世界。《阿弥陀经》《无量
寿经》里讲得清清楚楚，发菩提心后还要有足够的资粮才能往生。否则什么也没有，没
有菩提心，也没有积累资粮，往生是不可能的事！
胜义菩提心是通过修行才发出来的。资粮道、加行道都是生起胜义菩提心的基础与
条件。这些条件都具足了，这些基础都修好了，才能生起胜义菩提心。彻底弄明白了自
己的心，彻底见到了自己的本性，证悟本性，证悟空性了，这个时候就有无我的智慧，
就有证悟空性的智慧，才有胜义菩提心。胜义菩提心可以分十种，登地菩萨（一地菩萨
）到十地菩萨的发心都是胜义菩提心，之前都是世俗菩提心。
为修持成佛要发殊胜菩提心！
为度化一切父母众生要发誓修持成佛！
为早日圆成佛道要精进认真闻思修行！
想解脱成佛首先要发菩提心，发菩提心首先要发慈悲心。发慈悲心就是从内心里下
决心做决定：我一定要给予一切众生安乐、我一定要拔除一切众生痛苦！当这两种想法
特别强烈的时候才能发出来菩提心。之前都是在表面上、在形式上发的，实际上并没有
发出真正的菩提心。
我们知道，一切众生都当过自己的父母，都对我们有恩德。如果不报答这个恩德，
以后还要继续互相伤害、互相结怨。只有报答他们的恩德了，我们才可以解脱，才可以
成佛，才可以不再互相讨债还债了。我们特别地想报答这个恩德，然后从内心里下决心
做决定：我一定要给予一切众生安乐，这叫慈心；我一定要拔除一切众生的痛苦，这叫
悲心。这两者合在一起叫慈悲心。
那么怎样才能给予一切众生安乐？怎样才能拔除一切众生痛苦？那个时候，为了救
度一切众生发誓发愿要成佛的念头自然而然就有了，这叫发菩提心。所以在慈悲心的基
础上才能有真正的菩提心。
菩提心有很多种，分类如下：
（1）从心力分
从心力的角度来讲，菩提心可以分为像国王一样的发心、像舟子一样的发心和像牧
童一样的发心三种。心力就是心的力量，有的人心力大，有的人心力小。
像国王一样的发心。国王的想法是首先自己登上王位，然后再维护手下的臣民。这
种发心是自己先获得佛果，然后再救度众生，这叫广大意乐之发心，也被称为如国王式
发心，这种发心的心力属于下等。
像舟子一样的发心。舟子就是船夫。意思是自己和船上的游客一起，同时达到彼岸
。这种发心是自己和一切众生同时成佛，同时到达解脱的彼岸，超出轮回，获得正果。
这叫如舟子一样的殊胜智慧的发心。这种发心的心力属于中等。
像牧童一样的发心。牧童把牦牛赶在前面，自己在后面保护牦牛，让牦牛先到目的
地，然后自己再到。这种发心是自己不成佛，先将一切众生安置于佛果，然后自己再成
佛。这是最高、最殊胜，无与伦比的发心。这种发心的心力特别大，属于上等。就像地
藏王菩萨发的愿：“地狱不空，誓不成佛！”就是这种发心。
（2）从地道界限分
依照地道的界限来分，它可以分四种发心：胜解行发心、清净意乐发心、异熟发心
和断证发心。胜解行发心是资粮道、加行道的发心。一地菩萨到七地菩萨的发心是清净
意乐之发心。八地菩萨、九地菩萨、十地菩萨的发心是异熟之发心。佛断证圆满了，叫
断证发心。
（3）从发心本体分
从发心本体的角度来分，可以分两种，一个是世俗菩提心；另一个是胜义菩提心。
世俗菩提心是登地菩萨以下的发心；胜义菩提心是登地菩萨以上的发心。世俗菩提心可
以分两个：一个是愿菩提心；一个是行菩提心。愿菩提心和行菩提心都特别重要。
对于初学者来说世俗菩提心特别重要，尤其是愿菩提心特别重要。我们天天在讲法
、闻法前念的：“为度化一切父母众生要发誓修持成佛”，这是愿菩提心；“为早日圆
成佛道要精进认真闻思修行”，这是行菩提心。这两个都是菩提心，一个是为果而发誓
，一个是为因而发誓。
我们一定要反复地这样发愿，反复地这样发誓。直到有一天，我们的相续中自然而
然就有那么个念头、有那么个想法的时候，我们才算发出来菩提心。发出菩提心以后就
好了，那个时候修行一点也不难了，因为心到位了，一切都到位了。没有发心之前无论
修什么法、念什么佛都不会有真正的收获、不会有真正的成就，因为心没有到位。心不
到位，做什么事、修什么法都不到位。
我们要发菩提心，多多地发。有一天在我们的相续中有这个愿、有这个心了，就没
有这个“我”了，就只有菩提心了。然后我们的所作所为都是善事、都是为众生、都是
消业积福。行住坐卧都是修行的过程，吃喝玩乐都是修持的方法，每时每刻都能增加我
们的智慧与福报。因为现在有我执我爱，所以我们的所作所为都是为自己、都是烦恼分
别、都是执着、都是造业。
业障深重，不怕！当我们的相续中真正能够产生菩提心的时候，无论多重的业障都
会立即消失，无论多薄的福报都会立即增长。
我们念佛、持咒、诵经、求往生，因为没有发菩提心，所以无论念诵多少遍都没有
用，解脱不了！在发出菩提心的基础上，才能往生西方极乐世界。《阿弥陀经》《无量
寿经》里讲得清清楚楚，发菩提心后还要有足够的资粮才能往生。否则什么也没有，没
有菩提心，也没有积累资粮，往生是不可能的事！
胜义菩提心是通过修行才发出来的。资粮道、加行道都是生起胜义菩提心的基础与
条件。这些条件都具足了，这些基础都修好了，才能生起胜义菩提心。彻底弄明白了自
己的心，彻底见到了自己的本性，证悟本性，证悟空性了，这个时候就有无我的智慧，
就有证悟空性的智慧，才有胜义菩提心。胜义菩提心可以分十种，登地菩萨（一地菩萨
）到十地菩萨的发心都是胜义菩提心，之前都是世俗菩提心。
d*d
3 楼
A conversation with Robert Lefkowitz, Joseph Goldstein, and Michael Brown
Ushma S. Neill and Howard A. Rockman
Published May 1, 2012
Today we shift the format of our Conversations with Giants in Medicine and
allow three of our most charismatic giants (Robert Lefkowitz, Joseph
Goldstein, and Michael Brown) to interview each other (Figure 1). Lefkowitz
(Duke University) is known for his seminal discoveries in understanding G
protein–coupled receptor function. The legendary partnership between Brown
and Goldstein (University of Texas Southwestern Medical Center) has spanned
four decades. Together they were awarded the 1985 Nobel Prize in Physiology
or Medicine acknowledging their discovery of the LDL cholesterol receptor
and its role in the regulation of cholesterol metabolism. The full interview
can be seen on the JCI website, http://www.jci.org/kiosk/cgm.
Lefkowitz: I’m delighted to be here, particularly with two very close
friends and colleagues who have always been scientific heroes of mine. I
want to speak a little about our upbringing, since it is a little different
for all of us. I grew up in the Bronx and first developed an interest in
becoming a physician when I was in the third grade, inspired by my family
physician, who just captivated me. How did you both get started?
Goldstein: I was brought up in a town called Kingstree, South Carolina, that
had about maybe 3,500 people. I went to a high school that had 60 students.
In those days, there was complete segregation. It was an all-white high
school, but I had really good teachers who focused on reading, writing, and
arithmetic. And I had a great chemistry teacher. I guess that my first real
interest in science was chemistry in high school.
Brown: I was born in Brooklyn. My motivation for medicine came from my
father. He kept telling me that the only person who doesn’t have a boss is
a doctor. And in his community, the doctors were the highest, the most
respected people. And in high school, I became an amateur radio operator
building transmitters and receivers. And so, in the middle of the night,
plugging it in and blowing every fuse in the house, and then you had to go
back and sort of retrace your steps and figure out where you went wrong. And
that’s basically what I’ve done ever since in the lab.
Lefkowitz: At the time when I entered medical school, I really had no
serious intention of ever being a scientist. I mean, my goal was to be a
physician, just like the family physician who had inspired me. Was it your
thought you would become a biomedical scientist or that you would primarily
be a physician?
Goldstein: As medical students, we would inject patients with bromsulphalein
(BSP) to assess liver function. There was a complicated assay for the
conjugated form of BSP. I was making a standard curve of this BSP using the
spectrophotometer, and I had the wrong wavelength. I found something that my
professor, Burton Combs, who was looking over my shoulder, had never seen
before. To make a long story short, I figured out a way that one could
easily measure the conversion of BSP to BSP glutathione. And so, I wrote a
couple of papers on this as a medical student, and it was really my first
introduction to discovery. I was hooked on science.
Brown: I wanted to be a physician. But back in those days, in medical school
at University of Pennsylvania, the whole attitude was if you’re very good,
you’ll be a very good doctor. If you’re really great, you’ll be a
professor. And then, it was at the NIH where I got my first sort of eureka
moment. I was working in a lab with Earl Stadtman, and I made a chance
observation, and I got this kind of a sense of “Wow, this is incredible.”
It really doesn’t matter in retrospect how important the finding is. If you
can just have that eureka moment, no matter how trivial the finding is, and
appreciate that in that moment, you know something that nobody else knows.
Lefkowitz: Now, one of the most remarkable things about the two of you is
your scientific partnership. I’m curious: how did this partnership get
started, and how in the world did it persist all of these years?
Brown: When I was accepted at MGH, I was the first person in eleven years
from Penn that had been accepted, because it was the most competitive. There
were only twelve interns. A week later they sent a list of my fellow
interns. And there was this guy, Joe Goldstein from Southwestern Medical
College from Dallas, Texas. I thought it was a Bible school. And I figured,
well, if they’re accepting this guy, then maybe nobody applied this year.
Goldstein: Mike and I were both interns, and we were in the emergency room.
Those were the days when we were on every other night, and you really had to
work hard. Both of us were interested in metabolism at the time, and I
remember very specifically, we had a patient who came in with meningitis who
had lipodystrophy. And neither one of us knew very much about lipodystrophy
, so we started talking.
Brown: I remember admiring Joe’s intellect and experience very early.
Within the first two or three days of residency, it was clear that he knew
more than anybody else, not only in the internship group, but more than most
of the senior residents and half of the faculty. It was clear that this guy
was going someplace, and I just decided to ride along.
Lefkowitz: How did you come to the actual problem that you wanted to study?
Goldstein: We went to the NIH, all three of us were clinical associates,
even though we worked in labs. I worked in Marshall Nirenberg’s lab working
on the end stages of protein synthesis, but we also had to see patients.
Two of the first patients that I saw in the heart institute were this
brother and sister that had homozygous familial hypercholesterolemia (FH).
We came up with the idea that maybe the most logical defect would be in the
enzyme HMG-CoA reductase.
Brown: Well, let me just start by saying a word about NIH, because it meant
a lot to all three of us; it was magical. If you look at the achievements of
people who went through the NIH at that time, it is remarkable, and I think
it’s because of the culture.
Lefkowitz: I want to interject that in our group of clinical associates,
which was quite small, in addition to the three of us was Harold Varmus,
Alfred Gilman, Ferid Murad, Stan Prusiner, Ed Skolnik, and Tom Caskey.
Goldstein: All of us were spread on only two floors, and we were all MDs
with very little experience. And then, there were these giants, like
Marshall Nirenberg, Chris Anfinsen, Earl Stadtman, Ira Pastan, and Jesse
Roth.
Lefkowitz: Virtually almost the entirety of our generation of physicians who
became basic researchers emanated from that institution at that time. And
we all met each other. I know Joe was going back to Dallas because he had
basically been knighted by Don Seldin to come back there; what happened to
you, Mike? How did you wind up in Dallas?
Brown: Well, Joe kept telling me what a wonderful place Southwestern was.
And I met Seldin, and he was just the most imposing person I’d ever met.
Just in terms of erudition not only in medicine but also in science and was
incredibly inspirational. So, I decided to give Southwestern a try, even
though I still thought it was a Bible school. And we started working on HMG-
CoA reductase. But when Joe was in Seattle, he learned about tissue culture.
And so the idea was, we would study the regulation of the enzyme in
cultured fibroblasts from normal children and from children with FH. In fact
, Joe wrote a grant on this, and it was turned down because everybody said
the only important way to study cholesterol was in the liver, and we wanted
to study it in fibroblasts.
Goldstein: So, we got skin fibroblasts from a patient with FH, and Mike and
I began a ritual that we carried out, I would say at least for twenty years,
where we would meet every day and we would plan the experiments. And then
in those days, because we were both impatient, the cells would be harvested
and the assay would be done that same day, so we would know the results
quickly. The first experiment was comparing the HMG-CoA reductase activity
in those cells versus normal fibroblasts plus and minus LDL, and we got this
really dramatic result. There was a hundredfold difference in the presence
of LDL: the HMG-CoA reductase was a reflection of cholesterol synthesis.
Lefkowitz: If you look at our three careers, one thing that we have in
common is this element of focus. I often tell people that you could take
most of the experiments going on in my laboratory right now, and if you went
back to the experiment that led to that, and then the one that led to that,
and the one that led to that, you could go back to the day I opened my lab,
without any real jump.
Brown: The way I say it is that we never jump with two feet. We always keep
one foot on solid ground. If we are exploring new areas, we keep one foot on
solid ground. So, all of our work is really stemmed around cholesterol and
lipids in general.
Lefkowitz: Joe once told me something that I’ve passed along on a number of
occasions. I’m paraphrasing, but Joe once told me that the key to having
one good idea is to have a hundred bad ones and very quickly sort through
them to find that one gem. I guess that is what happens with the two of you.
Brown: The partnership does that automatically. But I always tell our
students, almost half jokingly, that 95% of the literature is wrong. The
other 5% was written by us.
Lefkowitz: This seems akin to something I often tell my people. There are
only three ways that people quote us: insufficiently, inappropriately, or
not at all.
Brown: What about mentoring? I mean, we all do a lot of it.
Goldstein: I think the best thing that I can say about mentoring is that if
you’re a good role model yourself, that’s the best way. Someone who is
passionate about his or her work, curious, dedicated, honest, has integrity
and is self-critical about data.
Lefkowitz: I very much endorse what you say about mentoring. The way to be a
mentor is to put yourself out there. I try to make myself as transparent as
possible. Anything that’s going on, watch me. It’s an apprenticeship,
right? More than anything else, it’s a matter of acquiring a certain sense
of taste, of integrity, of how do you do things. I guess one of the most
challenging things that we have to do is on the one hand, you need to
demonstrate rigor, and on the other, you need to demonstrate that even n = 1
can really turn you on because it gets you thinking. And I always make that
point. Often the fellows I find are resistant to show me some data. I’ll
say, “You got something.” They say, “Let me repeat it first.” Don’t
repeat it first, I want to know now!
Brown: I hate it when they don’t show us negative data.
Goldstein: We should hire you as a postdoctoral fellow.
Lefkowitz: I would love it. I want to conclude with one last story, which I
think illustrates a little bit about these two guys. Joe and I were once
flying from Dallas to San Francisco, and a gentleman recognized Joe. And he
says, “Oh my goodness! You’re Joe Goldstein, that famous doctor who won
the Nobel Prize. I read about you in the paper all the time, I’m so excited
about what you do,” and on and on. Joe just wanted to go under the chair.
But these guys are really celebrities, and they still are recognized both
among the scientific community and the lay community for everything they’ve
done.
Goldstein: It’s not as common as it used to be in Dallas — people would
always see me or Mike or both of us and say, “Oh, you’re the guy who won
the Peace prize.” We used to say, “No, we did this.” Now, we just say, “
Yeah.”
Brown: I’ll just extend with one other vignette. Very frequently, people
will call me Joe, and they’re always embarrassed, and I say, “Don’t be
embarrassed. My wife makes the same mistake.”
Ushma S. Neill and Howard A. Rockman
Published May 1, 2012
Today we shift the format of our Conversations with Giants in Medicine and
allow three of our most charismatic giants (Robert Lefkowitz, Joseph
Goldstein, and Michael Brown) to interview each other (Figure 1). Lefkowitz
(Duke University) is known for his seminal discoveries in understanding G
protein–coupled receptor function. The legendary partnership between Brown
and Goldstein (University of Texas Southwestern Medical Center) has spanned
four decades. Together they were awarded the 1985 Nobel Prize in Physiology
or Medicine acknowledging their discovery of the LDL cholesterol receptor
and its role in the regulation of cholesterol metabolism. The full interview
can be seen on the JCI website, http://www.jci.org/kiosk/cgm.
Lefkowitz: I’m delighted to be here, particularly with two very close
friends and colleagues who have always been scientific heroes of mine. I
want to speak a little about our upbringing, since it is a little different
for all of us. I grew up in the Bronx and first developed an interest in
becoming a physician when I was in the third grade, inspired by my family
physician, who just captivated me. How did you both get started?
Goldstein: I was brought up in a town called Kingstree, South Carolina, that
had about maybe 3,500 people. I went to a high school that had 60 students.
In those days, there was complete segregation. It was an all-white high
school, but I had really good teachers who focused on reading, writing, and
arithmetic. And I had a great chemistry teacher. I guess that my first real
interest in science was chemistry in high school.
Brown: I was born in Brooklyn. My motivation for medicine came from my
father. He kept telling me that the only person who doesn’t have a boss is
a doctor. And in his community, the doctors were the highest, the most
respected people. And in high school, I became an amateur radio operator
building transmitters and receivers. And so, in the middle of the night,
plugging it in and blowing every fuse in the house, and then you had to go
back and sort of retrace your steps and figure out where you went wrong. And
that’s basically what I’ve done ever since in the lab.
Lefkowitz: At the time when I entered medical school, I really had no
serious intention of ever being a scientist. I mean, my goal was to be a
physician, just like the family physician who had inspired me. Was it your
thought you would become a biomedical scientist or that you would primarily
be a physician?
Goldstein: As medical students, we would inject patients with bromsulphalein
(BSP) to assess liver function. There was a complicated assay for the
conjugated form of BSP. I was making a standard curve of this BSP using the
spectrophotometer, and I had the wrong wavelength. I found something that my
professor, Burton Combs, who was looking over my shoulder, had never seen
before. To make a long story short, I figured out a way that one could
easily measure the conversion of BSP to BSP glutathione. And so, I wrote a
couple of papers on this as a medical student, and it was really my first
introduction to discovery. I was hooked on science.
Brown: I wanted to be a physician. But back in those days, in medical school
at University of Pennsylvania, the whole attitude was if you’re very good,
you’ll be a very good doctor. If you’re really great, you’ll be a
professor. And then, it was at the NIH where I got my first sort of eureka
moment. I was working in a lab with Earl Stadtman, and I made a chance
observation, and I got this kind of a sense of “Wow, this is incredible.”
It really doesn’t matter in retrospect how important the finding is. If you
can just have that eureka moment, no matter how trivial the finding is, and
appreciate that in that moment, you know something that nobody else knows.
Lefkowitz: Now, one of the most remarkable things about the two of you is
your scientific partnership. I’m curious: how did this partnership get
started, and how in the world did it persist all of these years?
Brown: When I was accepted at MGH, I was the first person in eleven years
from Penn that had been accepted, because it was the most competitive. There
were only twelve interns. A week later they sent a list of my fellow
interns. And there was this guy, Joe Goldstein from Southwestern Medical
College from Dallas, Texas. I thought it was a Bible school. And I figured,
well, if they’re accepting this guy, then maybe nobody applied this year.
Goldstein: Mike and I were both interns, and we were in the emergency room.
Those were the days when we were on every other night, and you really had to
work hard. Both of us were interested in metabolism at the time, and I
remember very specifically, we had a patient who came in with meningitis who
had lipodystrophy. And neither one of us knew very much about lipodystrophy
, so we started talking.
Brown: I remember admiring Joe’s intellect and experience very early.
Within the first two or three days of residency, it was clear that he knew
more than anybody else, not only in the internship group, but more than most
of the senior residents and half of the faculty. It was clear that this guy
was going someplace, and I just decided to ride along.
Lefkowitz: How did you come to the actual problem that you wanted to study?
Goldstein: We went to the NIH, all three of us were clinical associates,
even though we worked in labs. I worked in Marshall Nirenberg’s lab working
on the end stages of protein synthesis, but we also had to see patients.
Two of the first patients that I saw in the heart institute were this
brother and sister that had homozygous familial hypercholesterolemia (FH).
We came up with the idea that maybe the most logical defect would be in the
enzyme HMG-CoA reductase.
Brown: Well, let me just start by saying a word about NIH, because it meant
a lot to all three of us; it was magical. If you look at the achievements of
people who went through the NIH at that time, it is remarkable, and I think
it’s because of the culture.
Lefkowitz: I want to interject that in our group of clinical associates,
which was quite small, in addition to the three of us was Harold Varmus,
Alfred Gilman, Ferid Murad, Stan Prusiner, Ed Skolnik, and Tom Caskey.
Goldstein: All of us were spread on only two floors, and we were all MDs
with very little experience. And then, there were these giants, like
Marshall Nirenberg, Chris Anfinsen, Earl Stadtman, Ira Pastan, and Jesse
Roth.
Lefkowitz: Virtually almost the entirety of our generation of physicians who
became basic researchers emanated from that institution at that time. And
we all met each other. I know Joe was going back to Dallas because he had
basically been knighted by Don Seldin to come back there; what happened to
you, Mike? How did you wind up in Dallas?
Brown: Well, Joe kept telling me what a wonderful place Southwestern was.
And I met Seldin, and he was just the most imposing person I’d ever met.
Just in terms of erudition not only in medicine but also in science and was
incredibly inspirational. So, I decided to give Southwestern a try, even
though I still thought it was a Bible school. And we started working on HMG-
CoA reductase. But when Joe was in Seattle, he learned about tissue culture.
And so the idea was, we would study the regulation of the enzyme in
cultured fibroblasts from normal children and from children with FH. In fact
, Joe wrote a grant on this, and it was turned down because everybody said
the only important way to study cholesterol was in the liver, and we wanted
to study it in fibroblasts.
Goldstein: So, we got skin fibroblasts from a patient with FH, and Mike and
I began a ritual that we carried out, I would say at least for twenty years,
where we would meet every day and we would plan the experiments. And then
in those days, because we were both impatient, the cells would be harvested
and the assay would be done that same day, so we would know the results
quickly. The first experiment was comparing the HMG-CoA reductase activity
in those cells versus normal fibroblasts plus and minus LDL, and we got this
really dramatic result. There was a hundredfold difference in the presence
of LDL: the HMG-CoA reductase was a reflection of cholesterol synthesis.
Lefkowitz: If you look at our three careers, one thing that we have in
common is this element of focus. I often tell people that you could take
most of the experiments going on in my laboratory right now, and if you went
back to the experiment that led to that, and then the one that led to that,
and the one that led to that, you could go back to the day I opened my lab,
without any real jump.
Brown: The way I say it is that we never jump with two feet. We always keep
one foot on solid ground. If we are exploring new areas, we keep one foot on
solid ground. So, all of our work is really stemmed around cholesterol and
lipids in general.
Lefkowitz: Joe once told me something that I’ve passed along on a number of
occasions. I’m paraphrasing, but Joe once told me that the key to having
one good idea is to have a hundred bad ones and very quickly sort through
them to find that one gem. I guess that is what happens with the two of you.
Brown: The partnership does that automatically. But I always tell our
students, almost half jokingly, that 95% of the literature is wrong. The
other 5% was written by us.
Lefkowitz: This seems akin to something I often tell my people. There are
only three ways that people quote us: insufficiently, inappropriately, or
not at all.
Brown: What about mentoring? I mean, we all do a lot of it.
Goldstein: I think the best thing that I can say about mentoring is that if
you’re a good role model yourself, that’s the best way. Someone who is
passionate about his or her work, curious, dedicated, honest, has integrity
and is self-critical about data.
Lefkowitz: I very much endorse what you say about mentoring. The way to be a
mentor is to put yourself out there. I try to make myself as transparent as
possible. Anything that’s going on, watch me. It’s an apprenticeship,
right? More than anything else, it’s a matter of acquiring a certain sense
of taste, of integrity, of how do you do things. I guess one of the most
challenging things that we have to do is on the one hand, you need to
demonstrate rigor, and on the other, you need to demonstrate that even n = 1
can really turn you on because it gets you thinking. And I always make that
point. Often the fellows I find are resistant to show me some data. I’ll
say, “You got something.” They say, “Let me repeat it first.” Don’t
repeat it first, I want to know now!
Brown: I hate it when they don’t show us negative data.
Goldstein: We should hire you as a postdoctoral fellow.
Lefkowitz: I would love it. I want to conclude with one last story, which I
think illustrates a little bit about these two guys. Joe and I were once
flying from Dallas to San Francisco, and a gentleman recognized Joe. And he
says, “Oh my goodness! You’re Joe Goldstein, that famous doctor who won
the Nobel Prize. I read about you in the paper all the time, I’m so excited
about what you do,” and on and on. Joe just wanted to go under the chair.
But these guys are really celebrities, and they still are recognized both
among the scientific community and the lay community for everything they’ve
done.
Goldstein: It’s not as common as it used to be in Dallas — people would
always see me or Mike or both of us and say, “Oh, you’re the guy who won
the Peace prize.” We used to say, “No, we did this.” Now, we just say, “
Yeah.”
Brown: I’ll just extend with one other vignette. Very frequently, people
will call me Joe, and they’re always embarrassed, and I say, “Don’t be
embarrassed. My wife makes the same mistake.”
e*e
4 楼
Sir. Madam.
【在 p*********a 的大作中提到】
: RT? 怎么称呼比较好？
【在 p*********a 的大作中提到】
: RT? 怎么称呼比较好？
W*N
5 楼
慈诚罗珠堪布慧灯之光
看过《俱舍论》的都知道，在世界刚刚诞生，人类繁衍之初，水、草、瓜果等等的
营养极其丰富。时至今日，所有食物的养分早已一落千丈，随着人心越来越凶恶，道德
越来越滑落，世上会不断地出现饥馑、疾疫、刀兵之灾，世界众生无不受害，故称之为
劫浊。 [慧灯之光六：《修心七要》略释 ]
看过《俱舍论》的都知道，在世界刚刚诞生，人类繁衍之初，水、草、瓜果等等的
营养极其丰富。时至今日，所有食物的养分早已一落千丈，随着人心越来越凶恶，道德
越来越滑落，世上会不断地出现饥馑、疾疫、刀兵之灾，世界众生无不受害，故称之为
劫浊。 [慧灯之光六：《修心七要》略释 ]
M*o
6 楼
Your Majesty, Your Highness
【在 e*****e 的大作中提到】
: Sir. Madam.
【在 e*****e 的大作中提到】
: Sir. Madam.
W*N
7 楼
慈诚罗珠堪布慧灯之光
所谓佛教，就是智慧和慈悲。慈悲和智慧不像衣食等商品，是不可能用钱去买卖交
易的。虽然在家人应该为弘扬佛法出些钱，但这并不是最重要的事情。如果真正想为佛
教做事情，就是要自己修行，之后尽量去传播真正的佛法。除此之外，那些身前身后的
浮云名利都是无关紧要的。[慧灯之光六：《修心七要》略释 ]
http://bbs.tianya.cn/post-16-650792-262.shtml [26133,26134 楼 ]
所谓佛教，就是智慧和慈悲。慈悲和智慧不像衣食等商品，是不可能用钱去买卖交
易的。虽然在家人应该为弘扬佛法出些钱，但这并不是最重要的事情。如果真正想为佛
教做事情，就是要自己修行，之后尽量去传播真正的佛法。除此之外，那些身前身后的
浮云名利都是无关紧要的。[慧灯之光六：《修心七要》略释 ]
http://bbs.tianya.cn/post-16-650792-262.shtml [26133,26134 楼 ]
M*P
8 楼
直接叫first name
★ 发自iPhone App: ChineseWeb 7.8
【在 p*********a 的大作中提到】
: RT? 怎么称呼比较好？
★ 发自iPhone App: ChineseWeb 7.8
【在 p*********a 的大作中提到】
: RT? 怎么称呼比较好？
i*m
9 楼
mark
a*u
10 楼
Shall I call you Firstname or Prof. Lastname?
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