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Today we know that women carrying BCRA1 and BCRA2 gene mutations have a 43% to 88% risk of developing from breast cancer before the age of 70. Taking critical decisions such as opting for preventive surgery when the risk bracket is so wide is not easy. Spanish National Cancer Research Centre (CNIO) researchers are conducting a study that will contribute towards giving every woman far more precise data about her personal risk of suffering from cancer.
The paper has been authored by 200 researchers from 55 research groups from around the world and describes two new genes that influence the risk of women developing breast and ovarian cancer when they are carriers of BCRA1 and BCRA2 mutations.
According to Ana Osorio, lead author of the study and a researcher in the Human Genetics Group, at CNIO: ‘The aim is to create a test that includes all known genetic variants that affect the risk of developing cancer, and at what age, in order to be able to compile a personalised profile for each patient.’ Osorio and Javier Benitez, the Director of the CNIO’s Human Cancer Genetics Programme, have jointly co-ordinated the work of all the participants in the study.
The finding is part of an international effort by the scientific community to get a more precise understanding of genomic information. Researchers are trying to identify genes associated with cancer as well as the reasons why the same mutated gene affects different people in different ways.
In the specific case of BRCA1 and BRCA2 genes, malfunctions may be caused by thousands of different mutations. However, the effects of these mutations can depend on other DNA variants found in other genes. These DNA variants may be caused by a single change in a chemical component from the 3 billion that make up the human genome. These single changes, known as SNPs (Single-nucleotide polymorphisms), do not inactivate genes and nor are they pathological in and of themselves, but they can play an important role when high-risk mutations already exist.
Understanding the genome to this degree of detail demands a lot of work. The weight of each risk-modulating element is small, so thousands of samples are needed for the effect to show in the data.
To do the work for the study that has been published, the researchers created a consortium called CIMBA (The Consortium of Investigators of Modifiers of BRCA1/2) in 2006, made up of research groups from around the world. CIMBA, with data from more than 40,000 carriers of BRCA1 and BRCA2 mutations, has the largest number of samples from which mutation interactions with SNPs can be studied.
Up to now, CIMBA has managed to associate more than 25 SNPs with the risk of developing breast or ovarian cancer in carriers of BRCA1/2 mutations. The study led by CNIO researchers adds at least two more to the list.
To find them, the study’s authors worked in two phases: they first analysed samples from 1,787 Spanish and Italian carriers of BRCA1/2 mutations, and managed to identify 36 potentially interesting SNPs; they later investigated their importance in a further 23,463 CIMBA samples. They thus discovered 11 SNPs that indicate risk, especially so in the case of two of them. Their influence is small—the largest risk multiplier is just 1.12—which is to say 12% on the base risk.
As Osorio explains: ‘The weight of each of these SNPs is very small, but with the 27 already described, the risk might increase or decrease for a woman who is a carrier of mutations.’
The newly discovered SNPs are in two genes known as NEIL2 and OGG1, and not by chance. The researchers went straight to the place where they found them. This way of working distinguishes this study from others that look for BRCA1/2 risk modulators by brute force: analysing and comparing everything to everything.
What advantages does searching with a compass offer? As well as being a more efficient strategy, it has allowed CNIO researchers to validate a hypothesis on how BRCA1/2 work. They also provide clues that might be useful for treatments already being used.
The hypothesis showed them where to look: in the genes of one of the DNA repair pathways. Cells have several ways to repair DNA, and one of them includes the use of BRCA1 and BRCA2 when they are non-mutated. If BRCA1 and BRCA2 do not fulfil their role because they are defective, another repair pathway takes over; if none of these pathways are functional the —cancerous— cell dies. So researchers hypothesised that there may be SNP risk modulators on this alternative repair route.
The hypothesis was correct. NEIL2 and OGG1, the genes that host the two SNPs that show the highest risk of developing cancer, intervene in the initiation of the alternative repair mechanism to BRCA1/2. ‘They are also basic genes for eliminating toxic waste generated by oxidative stress from cells,’ adds Benítez.
The result could also have interesting clinical implications. One of the drugs used against breast cancer that is associated to BRCA1 and BRCA2 mutations —called PARP inhibitors— acts by deactivating the alternative repair pathway. The authors therefore note in the study that: ‘These discoveries could have implications not only for determining risk but also in terms of treatment for carriers of BRCA1/2 mutations with PARP inhibitors.’ CNIO

Viruses cannot only cause illnesses in humans, they also infect bacteria. Those protect themselves with a kind of ‘immune system’ which – simply put – consists of specific sequences in the genetic material of the bacteria and a suitable enzyme. It detects foreign DNA, which may originate from a virus, cuts it up and thus makes the invaders harmless. Scientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig have now shown that the dual-RNA guided enzyme Cas9 which is involved in the process has developed independently in various strains of bacteria. This enhances the potential of exploiting the bacterial immune system for genome engineering.
Even though it has only been discovered in recent years the immune system with the cryptic name ‘CRISPR-Cas’ has been attracting attention of geneticists and biotechnologists as it is a promising tool for genetic engineering. CRISPR is short for Clustered Regularly Interspaced Palindromic Repeats, whereas Cas simply stands for the CRISPR-associated protein. Throughout evolution, this molecule has developed independently in numerous strains of bacteria. This is now shown by Prof Emmanuelle Charpentier and her colleagues at the Helmholtz Centre for Infection Research (HZI) who published their finding in the international open access journal Nucleic Acids Research.

The CRISPR-Cas-system is not only valuable for bacteria but also for working in the laboratory. It detects a specific sequence of letters in the genetic code and cuts the DNA at this point. Thus, scientists can either remove or add genes at the interface. By this, for instance, plants can be cultivated which are resistant against vermins or fungi. Existing technologies doing the same thing are often expensive, time consuming or less accurate. In contrast to them the new method is faster, more precise and cheaper, as fewer components are needed and it can target longer gene sequences.

Additionally, this makes the system more flexible, as small changes allow the technology to adapt to different applications. ‘The CRISPR-Cas-system is a very powerful tool for genetic engineering,’ says Emmanuelle Charpentier, who came to the HZI from Umeå and was awarded with the renowned Humboldt Professorship in 2013. ‘We have analysed and compared the enzyme Cas9 and the dual-tracrRNAs-crRNAs that guide this enzyme site-specifically to the DNA in various strains of bacteria.’ Their findings allow them to classify the Cas9 proteins originating from different bacteria into groups. Within those the CRISPR-Cas systems are exchangeable which is not possible between different groups.

This allows for new ways of using the technology in the laboratory: The enzymes can be combined and thereby a variety of changes in the target-DNA can be made at once. Thus, a new therapy for genetic disorders caused by different mutations in the DNA of the patient could be on the horizon. Furthermore, the method could be used to fight the AIDS virus HIV which uses a receptor of the human immune cells to infect them. Using CRISPR-Cas, the gene for the receptor could be removed and the patients could become immune to the virus. However, it is still a long way until this aim will be reached.

Still those examples show the huge potential of the CRISPR-Cas technology. ‘Some of my colleagues already compare it to the PCR,’ says Charpentier. This method, developed in the 1980s, allows scientists to ‘copy’ nucleic acids and therefore to manifold small amounts of DNA to such an extent that they can be analysed biochemically. Without this ground-breaking technology a lot of experiments we consider to be routine would have never been possible. Helmholtz Ceentre for Infection Research

Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness’s genetic causes, researchers at UCLA tried a new approach.

Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behaviour measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia’s University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioural measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.
A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they’re feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.

‘The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder,’ Bearden said. ‘This is an innovative approach to identifying genetically influenced brain and behavioural measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are.’
‘These findings are really just the first step in getting us a little closer to the roots of bipolar disorder,’ Bearden said. ‘What was really exciting about this project was that we were able to collect the most extensive set of traits associated with bipolar disorder ever assessed within any study sample. These data will be a really valuable resource for the field.’

The individuals assessed in this study are members of large families living in Costa Rica’s central valley and Antioquia, Colombia. The families were founded by European and native Amerindian populations about 400 years ago and have a very high incidence of bipolar disorder. The groups were chosen because they have remained fairly isolated since their founding and their genetics are therefore simpler for scientists to study than those of general populations. UCLA Health System

Extreme and traumatic events can change a person – and often, years later, even affect their children. Researchers of the University of Zurich and ETH Zurich have now unmasked a piece in the puzzle of how the inheritance of traumas may be mediated.
The phenomenon has long been known in psychology: traumatic experiences can induce behavioural disorders that are passed down from one generation to the next. It is only recently that scientists have begun to understand the physiological processes underlying hereditary trauma. ‘There are diseases such as bipolar disorder, that run in families but can’t be traced back to a particular gene’, explains Isabelle Mansuy, professor at ETH Zurich and the University of Zurich. With her research group at the Brain Research Institute of the University of Zurich, she has been studying the molecular processes involved in non-genetic inheritance of behavioural symptoms induced by traumatic experiences in early life.

Mansuy and her team have succeeded in identifying a key component of these processes: short RNA molecules. These RNAs are synthesised from genetic information (DNA) by enzymes that read specific sections of the DNA (genes) and use them as template to produce corresponding RNAs. Other enzymes then trim these RNAs into mature forms. Cells naturally contain a large number of different short RNA molecules called microRNAs. They have regulatory functions, such as controlling how many copies of a particular protein are made.

The researchers studied the number and kind of microRNAs expressed by adult mice exposed to traumatic conditions in early life and compared them with non-traumatised mice. They discovered that traumatic stress alters the amount of several microRNAs in the blood, brain and sperm – while some microRNAs were produced in excess, others were lower than in the corresponding tissues or cells of control animals. These alterations resulted in misregulation of cellular processes normally controlled by these microRNAs.

After traumatic experiences, the mice behaved markedly differently: they partly lost their natural aversion to open spaces and bright light and had depressive-like behaviours. These behavioural symptoms were also transferred to the next generation via sperm, even though the offspring were not exposed to any traumatic stress themselves.

The metabolism of the offspring of stressed mice was also impaired: their insulin and blood-sugar levels were lower than in the offspring of non-traumatised parents. ‘We were able to demonstrate for the first time that traumatic experiences affect metabolism in the long-term and that these changes are hereditary’, says Mansuy. The effects on metabolism and behaviour even persisted in the third generation.

‘With the imbalance in microRNAs in sperm, we have discovered a key factor through which trauma can be passed on,’ explains Mansuy. However, certain questions remain open, such as how the dysregulation in short RNAs comes about. ‘Most likely, it is part of a chain of events that begins with the body producing too much stress hormones.’

Importantly, acquired traits other than those induced by trauma could also be inherited through similar mechanisms, the researcher suspects. ‘The environment leaves traces on the brain, on organs and also on gametes. Through gametes, these traces can be passed to the next generation.’

Mansuy and her team are currently studying the role of short RNAs in trauma inheritance in humans. As they were also able to demonstrate the microRNAs imbalance in the blood of traumatized mice and their offspring, the scientists hope that their results may be useful to develop a blood test for diagnostics. ETH Zurich