WASHINGTONStanford University researchers have developed a
device for gene comparison that could lead to a more exact way to
categorize cancer tumors and assess the survival chances of patients.
In initial experiments with breast cancer patients, they detected
specific gene combinations in tumors and found that certain
combinations indicated either a good or bad prognosis.
We find that we can classify tumors into subsets, said
David Botstein, PhD, professor and chair of the Department of
Genetics, Stanford University School of Medicine.
Dr. Botstein described the new approach during a congressional
briefing on the importance of the computer to sequencing the human
genome and eventually using the information it contains to benefit
These two communities [genome mapping and computing], which
have revolutionized the way humans think about biology and how they
calculate, are converging, he said.
The briefing was one of a regular series held by the Congressional
Biomedical Research Caucus, a group of House members interested in
encouraging and promoting such research.
The important thing is that DNA is an information carrier,
Dr. Botstein said. It holds the information in a code of
nucleotide letters, and the cell decodes this into a protein for each
In computer terms, the human genome contains about 750 megabytes of
data. You all have laptops that can remember it, he
added. However, before you become impressed with the computer
industry, a cell that is 1 micron cubed has a nucleus that not only
remembers it, but uses all this information. So computers have a long
way to go to compete with biology.
Dr. Botstein noted that when the human genome is 100% sequenced (the
two competing groups doing the work still have some gaps to fill),
scientists will only have a string of letters from a book
that must be deciphered into meaningful words, which
represent genes. The sequence of the human genome, in some
nontrivial way, is absolutely useless as it now stands, he said.
To determine human genes and their functions, researchers compare
human genes with known genes of some other organism.
Sequence comparison essentially consists of looking for close
similarities in the genomes of two different organisms and selecting
the ones from each genome that most closely match one another,
Dr. Botstein said.
Yeast and eukaryocytes share many genes with humans, and the
functions of a number of these genes are known, he said. Work is
complete on several organisms, and the mouse genome is now in draft
form, he added.
Its not enough to have the human sequence, Dr.
Botstein explained. You must have these model organisms
sequences as well. When you have the complete sequences, you can do a
comparison of one whole genome against anotherall the
instructions for making a worm against all the instructions for
making a yeast.
Matching human genetic materials against those known in other species
will quicken the process of sorting the human genome sequences into
specific genes. By sequence comparison, we can tell which of
the human proteins does what, Dr. Botstein said. This is
extremely difficult and cannot be done without a computer.
Genes transcribe their code for making proteins into messenger RNA
(mRNA), which carries the message to cells, where proteins are
manufactured. When you know which messenger RNAs are in a cell,
then you know which proteins are being made, and when you know that,
then you know the nature of that cell, he said.
At Stanford, Patrick O. Brown, MD, PhD, a Howard Hughes Medical
Institute investigator collaborating with Dr. Botstein, has invented
a machine that makes thousands of mRNA copies and puts them on a
single slide. So on a single slide, we can have the entire
genome of an organism, Dr. Botstein said.
A gene expressed in a cell will make many copies of mRNA. And
if we have two cells and compare them, we can tell which gene is
expressed in one cell type compared to another cell type, he
said. And because we have this little gadget [invented by Dr.
Brown], we can do this for thousands of genes. If we are talking
about the yeast genome, thats 6,000 genes. If were
talking about the worm genome, thats 20,000 genes. And the
human genome is, who knows60,000?
In one experiment, the Stanford team looked at breast cancer samples
from a Norwegian study. In that trial, 20 women with late-stage
disease had surgery, followed by chemotherapy and then a second
surgery 16 weeks after the first to remove remaining tumor. Biopsies
samples were preserved at both operations.
Dr. Botstein and his colleagues analyzed the entire tumor and its
heterogeneous cell types from each biopsy. We boiled it down to
1,500 genes that changed by more than threefold on three different
assays, he said.
The really striking thing, he said, is that with very few
exceptions, the before and after samples are more similar to
each other than they are to anything else. So the tumor is stable and
orderly. Its not a mess. In all these genes, the level of
expression is more similar in the metastasis and the primary tumor
than the primary tumor or the metastasis is to anything else.
What that means, he said, is that when a cell migrates to a
lymph node, it createspresumably by signaling different parts
of the bodyan environment much like that of the primary tumor.
The team also found it could associate certain clusters of genes with
different kinds of tumor characteristics, such as the presence of
extensive T cells or B cells.
It turns out that if you go back into the records and see what
happened to these women. In one subset, nothing happened; these women
were still with us after 100 months, Dr. Botstein said. Another
subset, however, had extremely poor survival. Such findings make the
potential for using the technique to categorize tumors quite
promising, he added.